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Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index
Abstract
The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10(-5), Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10(-06)/Pfemales: 3.45 × 10(-07)/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.Molecular Psychiatry advance online publication, 17 May 2016; doi:10.1038/mp.2016.71.
... As the hypothalamus is the major regulator of appetite and energy homeostasis [25], we previously have investigated the effects of fasting and re-feeding on the hypothalamic expression of genes associated with an increased risk for AN and a decreased BMI (Ctbp2 and Nbeal1) [9]. Thus, functional ex-vivo studies in mice were conducted revealing that fasting led to a reduced hypothalamic expression of Ctbp2 (both transcriptional isoforms) and Nbeal1, while the expression of Ctbp2 in diet-induced obese (DIO) mice was upregulated in comparison to age-matched lean controls [9]. ...
... As the hypothalamus is the major regulator of appetite and energy homeostasis [25], we previously have investigated the effects of fasting and re-feeding on the hypothalamic expression of genes associated with an increased risk for AN and a decreased BMI (Ctbp2 and Nbeal1) [9]. Thus, functional ex-vivo studies in mice were conducted revealing that fasting led to a reduced hypothalamic expression of Ctbp2 (both transcriptional isoforms) and Nbeal1, while the expression of Ctbp2 in diet-induced obese (DIO) mice was upregulated in comparison to age-matched lean controls [9]. ...
... The mutation screen study group comprised 95 patients with AN (acute or recovered) [2] and 92 children and adolescents with severe obesity (86% with BMI percentile ≥ 97 th ). All participants were previously included in GWAS analyses with details pertaining the recruitment being described in the respective publications [9,38,[42][43][44]. Certain rare NSVs were genotyped in larger independent study groups of 367 patients with AN (acute or recovered), 398 children and adolescents with severe obesity (95% with BMI-percentile ≥ 97 th ), 445 healthy-lean (BMI-percentile ≤ 15 th ) and 168 individuals with a normal body weight (40 th ≤ BMI-percentile ≤ 60 th ; Table 1). ...
The C-terminal binding protein 2 (CTBP2) gene (translational isoforms: CTBP2-L/S, RIBEYE) had been identified by a cross-trait analysis of genome-wide association studies for anorexia nervosa (AN) and body mass index (BMI). Here, we did a mutation analysis in CTBP2 by performing polymerase chain reactions with subsequent Sanger-sequencing to identify variants relevant for AN and body weight regulation and ensued functional studies. Analysis of the coding regions of CTBP2 in 462 female patients with AN (acute or recovered), 490 children and adolescents with severe obesity, 445 healthy-lean adult individuals and 168 healthy adult individuals with normal body weight detected 24 variants located in the specific exon of RIBEYE. In the initial analysis, three of these were rare non-synonymous variants (NSVs) detected heterozygously in patients with AN (p.Arg72Trp - rs146900874; p.Val289Met -rs375685611 and p.Gly362Arg - rs202010294). Four NSVs and one heterozygous frameshift variant were exclusively detected in children and adolescents with severe obesity (p.Pro53Ser - rs150867595; p.Gln175ArgfsTer45 - rs141864737; p.Leu310Val - rs769811964; p.Pro397Ala - rs76134089 and p.Pro402Ser - rs113477585). Ribeye mRNA was detected in mouse hypothalamus. No effect of fasting or overfeeding on murine hypothalamic Ribeye expression was determined. Yet, increased Ribeye expression was detected in hypothalami of leptin-treated Lepob/ob mice. This increase was not related to reduced food intake and leptin-induced weight loss. We detected rare and frequent variants in the RIBEYE specific exon in both patients with AN and in children and adolescents with severe obesity. Our data suggest RIBEYE as a relevant gene for weight regulation.
... However, another possibility is that genes predisposing to higher BMI may also be linked to broader phenotypes relating to weight loss behaviors, even after accounting for BMI. Pleiotropy, when single genes affect more than one trait (Solovieff, Cotsapas, Lee, Purcell, & Smoller, 2013), has been demonstrated with certain genes predictive of BMI (Hinney et al., 2017). This was recently substantiated with the identification of three genetic loci that were involved with both BMI and anorexia nervosa (Hinney et al., 2017). ...
... Pleiotropy, when single genes affect more than one trait (Solovieff, Cotsapas, Lee, Purcell, & Smoller, 2013), has been demonstrated with certain genes predictive of BMI (Hinney et al., 2017). This was recently substantiated with the identification of three genetic loci that were involved with both BMI and anorexia nervosa (Hinney et al., 2017). However, there has been minimal research on the association between BMI PGS and weight loss behaviors. ...
... Previous work has identified three genetic loci that were involved with both BMI and anorexia nervosa (Hinney et al., 2017), indicating the potential for pleiotropy, when single genes may have two or more unrelated effects. However, when adjusting for BMI, we found that genetic risk for BMI was no longer independently associated with weight loss behaviors. ...
Background
The relationship between genetic risk for body mass index (BMI) and weight control behaviors remains unknown. The objectives of this study were to determine the association between genetic risk for BMI and weight control behaviors in young adults, and to examine actual measured BMI as a potential mediator variable.
Method
We analyzed data from three data collection waves of the National Longitudinal Study of Adolescent to Adult Health. The BMI polygenic score (PGS) was based on published genome‐wide association studies for BMI. BMI was collected at 11–18 years and 18–26 years. Weight control behaviors included self‐reported: (a) weight loss behaviors (dieting, vomiting, fasting/skipping meals, diet pills, laxatives, or diuretic use to lose weight) and (b) weight gain behaviors (eating more or different foods than normal, taking supplements to gain weight).
Results
Among 4,397 participants, the BMI PGS was associated with higher odds of weight loss behaviors in females (OR 1.24, 95% CI 1.14–1.35) and males (OR 1.43, 95% CI 1.26–1.62), and this association was mediated by BMI (indirect effect 0.04, 95% CI 0.03–0.05 in females and 0.03, 95% CI 0.03–0.04 in males). The BMI PGS was associated with lower odds of weight gain behaviors in females and males, which was also mediated by actual BMI.
Conclusions
The BMI PGS was associated with weight loss behaviors in both males and females, and this association was mediated by actual measured BMI. Clinical interventions to prevent high BMI, particularly for individuals with genetic risk, may also prevent subsequent development of potentially unhealthy weight loss behaviors.
... These incongruent findings could be influenced not only by disparate methodology but also by the age range of patients. Results from whole-brain approaches are mostly based on adolescent samples at an early stage of disease [24] or on mixed samples of adolescents and adults [8,25]. Given that brain development during adolescence follows a nonlinear course [26,27], it is particularly difficult to control for developmental influences. ...
... Twenty-eight women with severe AN (aged 18-32) and 40 HC (aged [18][19][20][21][22][23][24][25][26][27][28][29][30] participated in the study. One patient had to be excluded due to MRI artefacts, leaving the data of 27 women with AN (24 restrictive type, 3 binge-purge type) for analysis. ...
Altered intrinsic brain connectivity of patients with anorexia nervosa has been observed in the acute phase of the disorder, but it remains unclear to what extent these alterations recover during weight normalization. In this study, we used functional imaging data from three time points to probe longitudinal changes in intrinsic connectivity patterns in patients with severe anorexia nervosa (BMI ≤ 15.5 kg/m²) over the course of weight normalization. At three distinct stages of inpatient treatment, we examined resting-state functional connectivity in 27 women with severe anorexia nervosa and 40 closely matched healthy controls. Using network-based statistics and graph-theoretic measures, we examined differences in global network strength, subnetworks with altered intrinsic connectivity, and global network topology. Patients with severe anorexia nervosa showed weakened intrinsic connectivity and altered network topology which did not recover during treatment. The persistent disruption of brain networks suggests sustained alterations of information processing in weight-recovered severe anorexia nervosa.
... CtBP2 controls cellular processes by acting as a transcriptional corepressor, transcriptional activator and regulator of the cytoskeleton [13]. An intronic polymorphism within the CtBP2 gene, rs1561589, has been previously associated with BMI in females [14]. ...
... Our analysis of CtBP2 rs1561589 polymorphism also did not reveal a statistically significant association with any of the analyzed parameters. The same polymorphism was investigated in the genome-wide association study (GWAS) of Hinney et al. [14]. This study revealed the association of rs1561589 as well as two other intronic polymorphisms (rs126681170 and rs126674064) with susceptibility to anorexia nervosa and increased BMI, predominantly in females. ...
Introduction
Positive regulatory domain containing 16 (PRDM16) protein represents the key regulator of brown adipose tissue (BAT) development. It induces brown fat phenotype and represses white adipose tissue specific genes through the association with C-terminal binding co-repressor proteins (CtBP1 and CtBP2). In healthy adults presence of BAT has been associated with lower glucose, total cholesterol and LDL (low-density lipoprotein) cholesterol levels. Our aim was to analyze the association of PRDM16 gene (rs12409277) and CtBP2 gene (rs1561589) polymorphisms with body mass index (BMI), fasting glucose level and lipid profile of adolescents.
Material and methods
Our study included 295 healthy school children, 145 boys (49.2%) and 150 girls (50.8%), 15 years of age. Genotypes for the selected polymorphisms were detected by the real-time PCR method. Age, gender, height, weight, lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides) and fasting glucose levels were recorded.
Results
We did not find a statistically significant association of rs12409277 and rs1561589 polymorphisms with BMI, fasting glucose and lipid profile of adolescents. We further analyzed the combined effect of the two SNPs and the statistical analysis showed that carriers of CT genotype of rs12409277 polymorphism and GG genotype of rs1561589 polymorphism had significantly lower total cholesterol (p = 0.001) and LDL cholesterol (p = 0.008) levels compared to all other groups of genotypes.
Conclusions
Our study suggests that rs12409277 and rs1561589 polymorphism might have an influence on total and LDL cholesterol levels in adolescents. Larger studies should be performed in order to confirm our results.
... This association with obesity suggested that the alterations in methylation detected in the loci of NEGR1 are related to BMI in general and may be important for weight regulation. Some genetic studies have already shown this relationship to BMI at different loci [79,80]. ...
Anorexia nervosa (AN) is a complex metabolic and psychological disorder that is influenced by both heritable genetic components and environmental factors. Exposure to various environmental influences can lead to epigenetically induced changes in gene expression. Epigenetic research in AN is still in its infancy, and studies to date are limited in determining clear, valid links to disease onset and progression are limited. Therefore, the aim of this systematic review was to compile and critically evaluate the available results of epigenetic studies specifically in AN and to provide recommendations for future studies. In accordance with the PRISMA guidelines, a systematic literature search was performed in three different databases (PubMed, Embase, and Web of Science) through May 2023. Twenty-three original papers or conference abstracts on epigenetic studies in AN were collected. Epigenome-wide association studies (EWASs), which analyze DNA methylation across the genome in patients with AN and identify potential disease-relevant changes in promoter/regulatory regions of genes, are the most promising for future research. To date, five EWASs on AN have been published, suggesting a potential reversibility of malnutrition-induced epigenetic changes once patients recover. Hence, determining differential DNA methylation levels could serve as a biomarker for disease status or early diagnosis and might be involved in disease progression or chronification. For future research, EWASs with a larger sample size, longitudinal study design and uniform methods should be performed to contribute to the understanding of the pathophysiology of AN, the development of individual interventions and a better prognosis for affected patients.
... Temperament consists of the biological ingredients that define us and is neurobiologically expressed through our traits [22,35]. Traits influence actions. ...
Background
Temperament has long been described as the biological dimension of personality. Due to advancing brain-imaging technology, our understanding of temperament has deepened and transformed over the last 25 years. Temperament combines genetic, neurobiological and trait research. Temperament has been included peripherally in some eating disorder (ED) treatment approaches but has been ignored by most. Temperament fills a fundamental treatment gap by clarifying who is more vulnerable to develop ED and why some individuals are susceptible to specific ED symptoms while others are not. In addition, temperament targets possible treatment solutions.
Main text
There is a need for a novel model that incorporates and explores the role of temperament in ED treatment intervention. This paper is a metaphoric temperament model to inform treatment intervention. It describes how temperament traits influences new decisions which impact new behavioural responses. In turn, it neurobiologically tracks how and why the brain efficiently transforms new decisions into new habits. This model integrates both temperament and habit research to explore (a) what temperament is; (b) how new decisions develop into habits neurobiologically; (c) that the brain wires destructive symptoms into habits in the same way that it wires healthy/productive behaviours into habits; (d) traits that trigger ED symptoms are the same traits that influence productive behaviours; and in regard to treatment implications (e) when treatment structure and intervention target client temperaments, the potential for new healthy “trait-syntonic” habits could develop.
Conclusions
This paper introduces a metaphoric model that synthesizes and integrates temperament neurobiological and trait findings with ED symptoms, habits, and client trait-based solutions. The model synthesizes and integrates different research domains to establish a brain-based foundation to inform treatment intervention. The model targets clients’ temperament traits as central collections of innate self-expressions that could be utilized as tools to redirect client trait-syntonic ED responses into trait-syntonic productive outcomes. The brain bases of temperament and habit formation serve as a biological foundation for ED treatment intervention.
... By means of twin studies, a high heritability of AN up to 70 % could be manifested (Bulik et al., 2010;Mayhew et al., 2018;Trace et al., 2013). In addition, genome-wide association studies revealed a small number of genetic risk loci for AN (Hinney et al., 2017;Watson et al., 2019). Two types of AN can be clinically differentiated: a binge-eating/purging type and a restrictive type. ...
The brain-derived neurotrophic factor (BDNF) is a growth factor belonging to the neurotrophin family which plays a pivotal role in the differentiation, survival, and plasticity of neurons in the central nervous system. Evidence suggests that BDNF is an important signal molecule in the regulation of energy balance and thus implicated in body weight control. The discovery of BDNF-expressing neurons in the paraventricular hypothalamus which is important in the regulation of energy intake, physical activity, and thermogenesis gives more evidence to the suggested participation of BDNF in eating behavior. Until now it remains questionable whether BDNF can be used as a reliable biomarker for eating disorders such as anorexia nervosa (AN) as available findings on BDNF levels in patients with AN are ambiguous. AN is an eating disorder characterized by a pathological low body weight in combination with a body image disturbance typically developing during adolescence. A severe drive for thinness leads to restrictive eating behavior often accompanied by physical hyperactivity. During therapeutic weight restoration an increase of BDNF expression levels seems desirable as it might improve neuronal plasticity and survival which is essential for learning processes and thereby essential for the success of the psychotherapeutic treatment of patients. On the contrary, the well-known anorexigenic effect of BDNF might favor relapse in patients as soon as the BDNF levels significantly increase during weight rehabilitation. The present review summarizes the association between BDNF and general eating behavior and especially focuses on the eating disorder AN. In this regard findings from preclinical AN studies (activity-based anorexia model) are outlined as well.
... According to twin and other family studies, AN and BMI variation are both highly heritable [4][5][6][7]. Moreover, BMIassociated loci in part also have an effect on AN and vice versa [8]. Monogenic and/or polygenic genetic mechanisms can be relevant for both AN and BMI variation. ...
... In addition to genetic and environmental risk factors, the immune system is thought to play a pathophysiological role in AN (3,(18)(19)(20)(21)(22)(23)(24)(25). A dysregulated immune system due to impaired eating behavior or malnutrition has been shown to impair the activation and function of immune cells, which may have negative effects on the defense against pathogens (22,26). ...
Anorexia nervosa (AN) is a severe eating disorder characterized by excessive weight loss and lack of recognition of the seriousness of the current low body weight. Individuals with AN frequently exhibit an enhanced inflammatory state and altered blood levels of cytokines and chemokines. However, the expression of chemokine receptors in AN and the association with body composition parameters and treatment effects are still unknown. In this study, we examined the expression of CCR4, CCR6, CXCR3, and CXCR4 on peripheral blood T cells in female adolescents with AN before (T0, n = 24) and after 6 weeks of multimodal therapy (T1, n = 20). We also investigated their value to predict body mass index (BMI) and fat mass index (FMI) at baseline. Using multi-parameter flow cytometry, we found increased expression of CCR4, CXCR3, and CXCR4, but not CCR6, on CD4⁺ T cells in AN at T0 when compared to healthy controls (HC, n = 20). At T1, CXCR3 and CXCR4 expression decreased in AN. We found a close link between CCR4, CCR6 and CXCR4 expression and the adolescent mental health status in the study cohort as determined by the Strengths and Difficulties Questionnaire (SDQ). Specifically, CXCR4 expression correlated positively with emotional symptoms and peer relationship problems, as well as with the total sum score of the SDQ. In addition, CXCR4 expression on CD4⁺ T cells was a significant predictor of BMI and FMI in female adolescents. Our findings that CXCR4 expression on T cells is altered in adolescents with AN and predicts body composition parameters in adolescents suggest an impact of this chemokine receptor in the pathogenesis of AN.
... According to twin and other family studies, AN and BMI variation are both highly heritable [4][5][6][7]. Moreover, BMIassociated loci in part also have an effect on AN and vice versa [8]. Monogenic and/or polygenic genetic mechanisms can be relevant for both AN and BMI variation. ...
Genetic factors are relevant for both eating disorders and body weight regulation. A recent genome-wide association study (GWAS) for anorexia nervosa (AN) detected eight genome-wide significant chromosomal loci. One of these loci, rs10747478, was also genome-wide and significantly associated with body mass index (BMI). The nearest coding gene is the Polypyrimidine Tract Binding Protein 2 gene (PTBP2). To detect mutations in PTBP2, Sanger sequencing of the coding region was performed in 192 female patients with AN (acute or recovered) and 191 children or adolescents with (extreme) obesity. Twenty-five variants were identified. Twenty-three of these were predicted to be pathogenic or functionally relevant in at least one in silico tool. Two novel synonymous variants (p.Ala77Ala and p.Asp195Asp), one intronic SNP (rs188987764), and the intronic deletion (rs561340981) located in the highly conserved region of PTBP2 may have functional consequences. Ten of 20 genes interacting with PTBP2 were studied for their impact on body weight regulation based on either previous functional studies or GWAS hits for body weight or BMI. In a GWAS for BMI (Pulit et al. 2018), the number of genome-wide significant associations at the PTBP2 locus was different between males (60 variants) and females (two variants, one of these also significant in males). More than 65% of these 61 variants showed differences in the effect size pertaining to BMI between sexes (absolute value of Z-score >2, two-sided p < 0.05). One LD block overlapping 5′UTR and all coding regions of PTBP2 comprises 56 significant variants in males. The analysis based on sex-stratified BMI GWAS summary statistics implies that PTBP2 may have a more pronounced effect on body weight regulation in males than in females.
... Putative risk factors for EDs have been investigated, testing a wide range of environmental [29][30][31] and genetic factors [32,33]. A recent umbrella review of published meta-analyses, including 50 associations from nine meta-analyses, found evidence for childhood sexual abuse as a risk factor for BN and appearance-related teasing victimization for any ED [34]. ...
Obesity, eating disorders and unhealthy dieting practices among children and adolescents are alarming health concerns due to their high prevalence and adverse effects on physical and psychosocial health. We present the evidence that eating disorders and obesity can be managed or prevented using the same interventions in the pediatric age. In the presence of obesity in the pediatric age, disordered eating behaviors are highly prevalent, increasing the risk of developing eating disorders. The most frequently observed in subjects with obesity are bulimia nervosa and binge-eating disorders, both of which are characterized by abnormal eating or weight-control behaviors. Various are the mechanisms overlying the interaction including environmental and individual ones, and different are the approaches to reduce the consequences. Evidence-based treatments for obesity and eating disorders in childhood include as first line approaches weight loss with nutritional management and lifestyle modification via behavioral psychotherapy, as well as treatment of psychiatric comorbidities if those are not a consequence of the eating disorder. Drugs and bariatric surgery need to be used in extreme cases. Future research is necessary for early detection of risk factors for prevention, more precise elucidation of the mechanisms that underpin these problems and, finally, in the cases requiring therapeutic intervention, to provide tailored and timely treatment. Collective efforts between the fields are crucial for reducing the factors of health disparity and improving public health.
... Together with the structure-function relationships, it is an attracting and plausible possibility to identify CtBP2-activating small molecule(s) targeting the Rossmann fold, which is currently under extensive investigation. This idea is further supported by a genome wide association study showing the association of a human CtBP2 gene variant with body mass index, implicating the relevance of CtBP2 in human obesity 62 . ...
Biological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis. Here we describe a hepatic system in this context orchestrated by the transcriptional corepressor C-terminal binding protein 2 (CtBP2) that harbors metabolite-sensing capabilities. The repressor activity of CtBP2 is reciprocally regulated by NADH and acyl-CoAs. CtBP2 represses Forkhead box O1 (FoxO1)-mediated hepatic gluconeogenesis directly as well as Sterol Regulatory Element-Binding Protein 1 (SREBP1)-mediated lipogenesis indirectly. The activity of CtBP2 is markedly defective in obese liver reflecting the metabolic perturbations. Thus, liver-specific CtBP2 deletion promotes hepatic gluconeogenesis and accelerates the progression of steatohepatitis. Conversely, activation of CtBP2 ameliorates diabetes and hepatic steatosis in obesity. The structure-function relationships revealed in this study identify a critical structural domain called Rossmann fold, a metabolite-sensing pocket, that is susceptible to metabolic liabilities and potentially targetable for developing therapeutic approaches.
... B. BMI) analysiert. So konnten durch einen Abgleich der 1000 SNPs mit den niedrigsten p-Werten einer GWAS zur AN (Boraska et al., 2014) mit den Befunden einer GWAS zum BMI (Speliotes et al., 2010) drei genomische Regionen identifi ziert werden, die für beide Störungen von Bedeutung sind (Hinney et al., 2017). Interessanterweise wird dabei, passend zur Geschlechterwendigkeit der AN, der größte (statistische) Eff ekt für einen BMI-SNP auf Chromosom 10 (r1561589) v. a. durch die Befunde bei Frauen vermittelt. ...
Zusammenfassung. Genetische Varianten beeinflussen die Gewichtsregulation und die Entwicklung von Essstörungen. Zunächst haben familienbasierte, sogenannte formalgenetische Studien den erblichen Anteil an der Gewichtsregulation und an der Ätiologie von Essstörungen beleuchtet. In einer Vielzahl von Studien zeigten sich sowohl für die Varianz des Körpergewichts als auch für die Entstehung von Essstörungen Erblichkeitsschätzer (Heritabilitätsraten) von über 50 %. Mit diesem Wissen begab man sich in den 90er-Jahren des letzten Jahrhunderts auf die Suche nach den zugrundeliegenden Genen (genauer: genetischen Varianten), die das Körpergewicht, das Essverhalten oder beide Phänotypen auf Grundlage geteilter Mechanismen beeinflussen. Zunächst wurden Kandidatengenstudien durchgeführt. Dabei untersuchte man auf Grundlage unterschiedlicher, v. a. aber pathophysiologisch plausibler Überlegungen Gene mit hoher Relevanz für die untersuchten Phänotypen. Dieser Ansatz war für Essstörungen nicht sehr erfolgreich, für die Gewichtsregulation konnte eine Handvoll Gene identifiziert werden. Verbunden mit großen methodischen Fortschritten in der genetischen Forschung und v. a. der Etablierung sogenannter genomweiter Assoziationsstudien (GWAS) Anfang der 2000er-Jahre konnten bislang über 1000 Varianten/Genorte detektiert werden, die das Körpergewicht beeinflussen. Für die Essstörung Anorexia nervosa (AN) sind aktuell acht solcher Genorte beschrieben. Diese Ergebnisse, aber auch aktuelle Ansätze zu phänotypübergreifenden Analysen lassen Einblicke in die komplexe Regulation des Körpergewichtes zu und haben zudem unerwartete Pathomechanismen für AN aufgezeigt.
... So zeigte sich, dass einzelne Risiko-Allele für Adipositas gleichzeitig mit psychischen Störungen wie ADHS (Albayrak et al., 2013) und Alzheimer Demenz (Hinney et al., 2014) zusammenhängen. Eine Look-up-Analyse der 1000 SNPs mit den niedrigsten p-Werten in GWAS zu Anorexia nervosa ergab für Varianten an drei chromosomalen Loci einen potenziellen Einfl uss auf den Body-Mass-Index (BMI; Hinney et al., 2017). Dieses Ergebnis war u. a. vor dem Hintergrund, dass zu diesem Zeitpunkt keine genomweit signifi kanten Loci für AN bekannt waren, besonders interessant. ...
Zusammenfassung. Einleitung: Klassische ernährungsepidemiologische Studien (Beobachtungsstudien und randomisierte Interventionsstudien) zeigen, dass die Ernährung ein wichtiger Ansatzpunkt für die Prävention und Therapie psychischer Störungen sein könnte. Diese Studientypen haben allerdings Limitationen, die bei der Ergebnisinterpretation berücksichtigt werden müssen. In dieser narrativen übersichtsarbeit wird beschrieben, wie genetische Studien ein Bindeglied darstellen können, um einen Zusammenhang zwischen Ernährung und psychischen Störungen herzustellen. Methodik: Im Artikel werden verschiedene Ansätze genetischer phänotypübergreifender Analysen sowie Beispiele für deren Anwendungen in der ernährungspsychiatrischen Forschung beschrieben. Darüber hinaus werden spezifische Voraussetzungen sowie Stärken und Schwächen diskutiert. Ergebnisse: Als Methoden genetischer phänotypübergreifender Analysen sind im Rahmen ernährungspsychiatrischer Forschung bislang genetische Korrelationsanalysen, Look-up-Analysen sowie Mendelsche Randomisierungsstudien (MR-Studien) eingesetzt worden. Genetische Korrelationsanalysen und Look-up-Analysen geben erste Hinweise auf mögliche genetische überlappungen zwischen einer psychischen Störung und einem Stoffwechselweg und/oder der Versorgung mit einem spezifischen Nährstoff. MR-Studien sind weitergehende Detailanalysen mit dem Ziel, Kausalzusammenhänge zu identifizieren, beinhalten allerdings sehr spezifische Grundvoraussetzungen für ihre Durchführung. Schlussfolgerung: Genetische phänotypübergreifende Analysen sind eine sinnvolle Ergänzung der klassischen Ernährungsepidemiologie. Insbesondere signifikante Ergebnisse von MR-Studien sind eine wichtige Grundlage zur Entwicklung geeigneter Ernährungsinterventionen, die in nachfolgenden randomisiert kontrollierten Interventionsstudien mit deutlich erhöhter Erfolgsaussicht getestet werden können. Sie sind somit wichtige Instrumente einer effizienten ernährungspsychiatrischen Forschung.
... For instance, nine SNPs at three loci (C-terminal binding protein 2 [CTBP2], cyclin E1 [CCNE1], and calcium responsive transcription factor/neurobeachin like-1 [CARF/NBEAL1]) have been shown to be related to anorexia nervosa(181), but these loci have not been implicated in healthy thin individuals thus far. Likewise, a duplication of an approximately 600 kb region on chromosome 16 (16:29.5-30.1) is associated with low body weight in children and adults who tend to exhibit developmental disabilities or psychiatric disorders(182). ...
There is a genetic component to human obesity that accounts for 40% to 50% of the variability in body weight status but that is lower among normal weight individuals (about 30%) and substantially higher in the subpopulation of individuals with obesity and severe obesity (about 60%-80%). The appreciation that heritability varies across classes of BMI represents an important advance. After controlling for BMI, ectopic fat and fat distribution traits are characterized by heritability levels ranging from 30% to 55%. Defects in at least 15 genes are the cause of monogenic obesity cases, resulting mostly from deficiencies in the leptin-melanocortin signaling pathway. Approximately two-thirds of the BMI heritability can be imputed to common DNA variants, whereas low-frequency and rare variants explain the remaining fraction. Diminishing allele effect size is observed as the number of obesity-associated variants expands, with most BMI-increasing or -decreasing alleles contributing only a few grams or less to body weight. Obesity-promoting alleles exert minimal effects in normal weight individuals but have larger effects in individuals with a proneness to obesity, suggesting a higher penetrance; however, it is not known whether these larger effect sizes precede obesity or are caused by an obese state. The obesity genetic risk is conditioned by thousands of DNA variants that make genetically based obesity prevention and treatment a major challenge.
... Fourth, the identification of significant negative correlations between AN and BMI-related and anthropometric measures could potentially serve as an important first step toward gaining a better understanding of the shared biology underlying extremes of weight dysregulation (i.e., obesity vs. AN). As noted by Bulik-Sullivan et al. 12 and Hinney et al. 20 , these results extend our understanding that the same genetic factors that influence normal variation in BMI, body shape, and body composition may also influence extreme dysregulation of these weight-related features in AN. This pattern of observations complements prior strong evidence for the involvement of Finally, also worthy of further investigation are the numerous immune-related phenotypic associations nearby our top locus for AN. ...
Anorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females1,2, and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality2. Twin studies support a genetic basis for the observed aggregation of AN in families3, with heritability estimates of 48%-74%4. Although initial genome-wide association studies (GWASs) were underpowered5,6, evidence suggested that signals for AN would be detected with increased power5. We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10−9) in a region (chr12:56,372,585-56,482,185) which includes six genes. The SNP-chip heritability
of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation. Using these GWAS results, we also find significant positive genetic correlations with schizophrenia, neuroticism, educational attainment, and HDL cholesterol, and significant negative genetic correlations with body mass, insulin, glucose, and lipid phenotypes. Our results support the reconceptualization of AN as a disorder with both psychiatric and metabolic components.
... [7][8][9] The fact that there is no clearly superior psychosocial intervention among a wide range of interventions for adults and adolescents with AN is also particularly concerning. 10 Despite the poor mechanistic knowledge of ED, an extensive body of literature has investigated putative risk factors for ED, testing a wide range of environmental [11][12][13][14][15] and genetic [16][17][18][19][20] risk factors. However, the contrasting results of individual studies are frequently not confirmed in meta-analysis. ...
Objective: To grade the evidence about risk factors for eating disorders (anorexia nervosa, bulimia nervosa, and binge eating disorder) with an umbrella review approach.
Methods: This was a systematic review of observational studies on risk factors for eating disorders published in PubMed/PsycInfo/Embase until December 11th, 2019. We recalculated random-effect meta-analyses, heterogeneity, small-study effect, excess significance bias and 95% prediction intervals, grading significant evidence (p < 0.05) from convincing to weak according to established criteria. Quality was assessed with the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2) tool.
Results: Of 2,197 meta-analyses, nine were included, providing evidence on 50 risk factors, 29,272 subjects with eating disorders, and 1,679,385 controls. Although no association was supported by convincing evidence, highly suggestive evidence supported the association between childhood sexual abuse and bulimia nervosa (k = 29, 1,103 cases with eating disorders, 8,496 controls, OR, 2.73, 95%CI 1.96-3.79, p = 2.1 x 10-9, AMSTAR-2 moderate quality) and between appearance-related teasing victimization and any eating disorder (k = 10, 1,341 cases with eating disorders, 3,295 controls, OR 2.91, 95%CI 2.05-4.12, p = 1.8x10-9, AMSTAR-2 moderate quality). Suggestive, weak, or no evidence supported 11, 29, and 8 associations, respectively.
Conclusions: The most credible evidence indicates that early traumatic and stressful events are risk factors for eating disorders. Larger collaborative prospective cohort studies are needed to identify risk factors for eating disorders, particularly anorexia nervosa.
... Findings from our group have also previously implicated BMI-related genes in adolescent binge eating in this sample [51]. Taken together, our data and those of others support the notion of a shared genetic etiology between DE and propensity for higher BMI [27,51,57]. ...
Background:
Disordered eating (DE) is common and is associated with body mass index (BMI). We investigated whether genetic variants for BMI were associated with DE. Methods: BMI polygenic scores (PGS) were calculated for participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 8654) and their association with DE tested. Data on DE behaviors (e.g., binge eating and compensatory behaviors) were collected at ages 14, 16, 18 years, and DE cognitions (e.g., body dissatisfaction) at 14 years. Mediation analyses determined whether BMI mediated the association between the BMI-PGS and DE. Results: The BMI-PGS was positively associated with fasting (OR = 1.42, 95% CI = 1.25, 1.61), binge eating (OR = 1.28, 95% CI = 1.12, 1.46), purging (OR = 1.20, 95% CI = 1.02, 1.42), body dissatisfaction (Beta = 0.99, 95% CI = 0.77, 1.22), restrained eating (Beta = 0.14, 95% CI = 0.10, 1.17), emotional eating (Beta = 0.21, 95% CI = 0.052, 0.38), and negatively associated with thin ideal internalization (Beta = -0.15, 95% CI = -0.23, -0.07) and external eating (Beta = -0.19, 95% CI = -0.30, -0.09). These associations were mainly mediated by BMI. Conclusions: Genetic variants associated with BMI are also associated with DE. This association was mediated through BMI suggesting that weight potentially sits on the pathway from genetic liability to DE.
... The derivative-associated genetic loci overlap between anorexia and variation of body mass index [122]. It is possible that anorexia and bulimia may be the bilateral extreme tails of a continuous distribution whose latent spectrum is the main derivative-related dimension. ...
How a social episode is perceived by a person and how the experience affects her/his subsequent behaviors will inevitably and sometimes accidentally vary in each case on the developmental trajectory from the birth of consciousness to death. Both the preceding developmental conditions and the social impact of the episode become a starting point for the following states of human complex conditions, creating the extraordinary diversity that characterizes our complex society. In this evolutionarily carved landscape, genetic factors including stochastic epistasis, environmental modification, and gene-environment interactions are all active. In these processes, interactions between developmental social vulnerability and environmental influences can lead to the emergence and persistence of some derivative states with social maladaptation. In our model, every psychiatric condition including aberrant paranoid-hallucinatory states is classified as a derivative state. The probability distribution curve for these derivative states has a non-linear relationship with the liability in the population, and there is none with probability 1.0 or zero. Individuals with trivial social vulnerability or high resilience may develop the derivative states in tremendously stressful circumstances, and individuals with huge social vulnerability may not necessarily develop the derivative states in the presence of adequate social supports. Social skillfulness/unskillfulness and behavioral flexibility/inflexibility form the core of the vulnerability-related dimensions. The clinical picture of a derivative manifestation is profiled depending on the individual trait levels in the derivative-related dimensions. Each derivative state has a requisite lineup of dimensions and each dimension can contribute to multiple psychiatric conditions. For example, aberrant paranoid-hallucinatory states and bipolar condition may share some developmental conditions as the derivative-related dimensions. Therefore, multiple derivative states can co-occur or be sequentially comorbid. Although the 'learned strategies' can ostensibly mask the clinical manifestation of developmental deviations, the change of the true dimensional position to the socially skillful direction is efficiently obtained through social experiences in a supportive environment. The liability-probability model makes it impossible to discriminate individuals with psychiatric diagnosis from individuals without the diagnosis and allows all of us to reside in the same human complex diversity.
... 17 Recent advances in the understanding of these factors include those within the areas of neurobiology, immunology, and genetics. [18][19][20][21][22] A growing body of evidence suggests involvement of metabolic processes in the development of AN, including appetite-satiety pathways. For example, 2 large genome-wide association studies of AN have found not just positive genetic correlations with other mental disorders but also with metabolic parameters, such as high-density lipoprotein cholesterol and significant negative genetic correlations with body mass index, insulin, glucose, and lipid phenotypes. ...
Over the last 50 years, in parallel with the obesity epidemic, the prevalence of eating disorders has increased and presentations have changed. In this narrative review, we consider recent research exploring the implications of changing patterns of food consumption on metabolic and neurobiological pathways, a hitherto neglected area in eating disorder research. One of the major changes over this time has been the introduction of ultra-processed (NOVA-4) foods, which are gradually replacing unprocessed and minimally processed foods. This has resulted in the increased intake of various sugars and food additives worldwide, which has important metabolic consequences: triggering insulin and glucose response, stimulating appetite, and affecting multiple endocrine and neurobiological pathways, as well as the microbiome. A paradigm shift is needed in the conceptual framework by which the vulnerability to, and maintenance of, different eating disorders may be understood, by integrating recent knowledge of the individual metabolic responses to modern highly processed foods into existing psychological models. This could stimulate research and improve treatment outcomes.
... Additionally, we used meta-analytic publicly available data from the GIANT (Genetic Investigation of Anthropometric Traits) Consortium, covering around 700,000 individuals of European ancestry in the context of body mass index (BMI) [117], to analyze HDAC4 in relation to BMI. An overlap between single-nucleotide polymorphisms (SNPs) associated with BMI and AN has been previously reported [118]. Although HDAC4 was not among the 941 SNPs associated with BMI at a genome-wide significance threshold (p < 1 × 10-8), the left-skewed distribution of the p-values of 234 SNPs within the HDAC4 gene indicates a relatively high proportion of lower p-values, encouraging to further explore HDAC4 in BMI regulation (Supplementary Fig. 1 and Supplementary Table 2). ...
Anorexia nervosa (AN) and other eating disorders continue to constitute significant challenges for individual and public health. AN is thought to develop as a result of complex interactions between environmental triggers, psychological risk factors, sociocultural influences, and genetic vulnerability. Recent research developments have highlighted a novel potentially relevant component in the AN etiology—activity of the histone deacetylase 4 (HDAC4) gene that has emerged in several recent studies related to AN. HDAC4 is a member of the ubiquitously important family of epigenetic modifier enzymes called histone deacetylases and has been implicated in processes related to the formation and function of the central nervous system (CNS), bone, muscle, and metabolism. In a family affected by eating disorders, a missense mutation in HDAC4 (A786T) was found to segregate with the illness. The relevance of this mutation in eating-related behaviors was further confirmed with mouse models. Despite the fact that HDAC4 has not been identified as a significant signal in genome-wide association studies in AN, several studies have found significant or near-significant methylation differences in HDAC4 locus in peripheral tissues of actively ill AN patients in comparison with different control groups. Limitations of these studies include a lack of understanding of to what extent the changes in methylation are predictive of AN as such changes might also occur as a consequence of the disease. It remains to be determined how methylation in peripheral tissues correlates with that in the CNS and how different methylation patterns affect HDAC4 expression. The present review discusses the findings and potential roles of HDAC4 in AN. Its emerging roles in learning and neuroplasticity may be specific and relevant for the etiology of AN and potentially lead to novel therapeutic approaches.
... It has been speculated that hunger signals are diminished or even absent in individuals with AN, and that satiety signals on the other hand are exaggerated (DeBoer, 2011;Oberndorfer et al., 2013). Supporting this hypothesis, a genome wide association study (GWAS), as well as genetic correlation data, indicate that individuals with AN are genetically predisposed to a lower body weight set point ( Duncan et al., 2017;Hinney et al., 2017). However, in order to understand the complex biology of AN, in particular the illogical response to starvation and underweight, we need to learn more about the neurobiological pathways and molecular mechanisms that are associated with severe dysregulation of food intake. ...
Animal models are invaluable resources in research concerning the neurobiology of anorexia nervosa (AN), to a large extent since valid clinical samples are rare. None of the existing models can capture all aspects of AN but they are able to mirror the core features of the disorder e.g., elective starvation, emaciation and premature death. The anorectic anx/anx mouse is of particular value for the understanding of the abnormal response to negative energy balance seen in AN. These mice appear normal at birth but gradually develops starvation and emaciation despite full access to food, and die prematurely around three weeks of age. Several changes in hypothalamic neuropeptidergic and -transmitter systems involved in regulating food intake and metabolism have been documented in the anx/anx mouse. These changes are accompanied by signs of inflammation and degeneration in the same hypothalamic regions; including activation of microglia cells and expression of major histocompatibility complex I by microglia and selective neuronal populations. These aberrances are likely related to the dysfunction of complex I (CI) in the oxidative phosphorylation system of the mitochondria, and subsequent increased oxidative stress, which also has been revealed in the hypothalamus of these mice. Interestingly, a similar CI dysfunction has been shown in leukocytes from patients with AN. In addition, a higher expression of the Neurotrophic Receptor Tyrosine Kinase 3 gene has been shown in the anx/anx hypothalamus. This agrees with AN being associated with specific variants of the genes for brain derived neurotrophic factor and Neurotrophic Receptor Tyrosine Kinase 2. The anx/anx mouse is also glucose intolerant and display pancreatic dysfunction related to increased levels of circulating free fatty acids (FFA) and pancreatic inflammation. An increased incidence of eating disorders has been reported for young diabetic women, and as well has increased levels of circulating FFAs in AN. Also similar to individuals with AN, the anx/anx mouse has reduced leptin and increased cholesterol levels in serum. Thus, the anx/anx mouse shares several characteristics with patients with AN, including emaciation, starvation, premature death, diabetic features, increased FFA and low leptin, and is therefore a unique resource in research on the (neuro)biology of AN.
... In females, there appears to be shared genetic predisposition for early menarche and the onset of disordered eating [51]. Genes responsible for estrogen and food intake also account for some of the shared genetic factors for early menarche [52]. Estrogen plays role in regulating the genes responsible for brain derived neurotropic factor and the serotonin system, both of which are associated with ED symptoms [53,54]. ...
Purpose of Review
We review research related to sex differences in eating disorders (EDs) in adolescents. Prior work has explored clinical differences; thus, we examine literature in areas identified as playing an etiological or maintenance role in EDs including: genetics, hormones, neurocognitive inefficiencies, and reward circuitry.
Recent Findings
Sex steroids appear to a play role in the unmasking of genetic risk for development of EDs and puberty may be a heightened period of risk for females. While neurocognitive differences have been well studied in adults with ED, research with adolescents has been less conclusive. Recent work suggests that neural circuitry involved in reward and punishment may play role in development and maintenance of EDs in females. Males are underrepresented in these areas of research.
Summary
Given known sex differences in healthy adolescents, it is likely there are sex differences in the putative biological etiology/maintenance of EDs. Males should be included in future research.
... Furthermore, AN shares common genetic variation with metabolic traits, such as insulin sensitivity and cholesterol. This revealed, for the first time, that a component of the genetic risk for AN is related to body composition and metabolism (Duncan et al., 2017;Hinney et al., 2017). ...
Anorexia nervosa (AN) occurs nine times more often in females than in males. Although environmental factors likely play a role, the reasons for this imbalanced sex ratio remain unresolved. AN displays high genetic correlations with anthropometric and metabolic traits. Given sex differences in body composition, we investigated the possible metabolic underpinnings of female propensity for AN. We conducted sex‐specific GWAS in a healthy and medication‐free subsample of the UK Biobank (n = 155,961), identifying 77 genome‐wide significant loci associated with body fat percentage (BF%) and 174 with fat‐free mass (FFM). Partitioned heritability analysis showed an enrichment for central nervous tissue‐associated genes for BF%, which was more prominent in females than males. Genetic correlations of BF% and FFM with the largest GWAS of AN by the Psychiatric Genomics Consortium were estimated to explore shared genomics. The genetic correlations of BF%male and BF%female with AN differed significantly from each other (p < .0001, δ = −0.17), suggesting that the female preponderance in AN may, in part, be explained by sex‐specific anthropometric and metabolic genetic factors increasing liability to AN.
... However, genome-wide association studies have yet to identify genetic risk factors associated with BE (4). The first genome-wide significant loci for anorexia nervosa (comprising restricted eating) were recently identified (5) and genome-wide significant loci are expected to soon be uncovered for BE-associated disorders with increasing sample sizes and power (6). ...
Binge eating (BE) is a heritable trait associated with eating disorders and involves consumption of a large quantity of food in a short time. We identified cytoplasmic FMRP-interacting protein 2 (Cyfip2) as a major genetic factor underlying BE and concomitant compulsive-like behaviors in mice. CYFIP2 is a gene homolog of CYFIP1-one of four paternally deleted genes in patients with the more severe Type I Prader-Willi Syndrome (PWS). PWS is a neurodevelopmental genetic disorder where 70% of cases involve paternal deletion of 15q11-q13. PWS is defined phenotypically by the emergence of hyperphagia and obesity during childhood as well as cognitive deficits and obsessive-compulsive behaviors. We tested the hypothesis that Cyfip1 haploinsufficiency would enhance premorbid compulsive-like behavior and palatable food (PF) consumption in a parent-of-origin-selective manner. Additionally, because our initial studies involved mice on a C57BL/6N background that possess the BE-associated missense mutation in Cyfip2, we tested mice on a mixed background where mice were homozygous for the C57BL/6J (B6J) allele at the Cyfip2 locus. Cyfip1 haploinsufficiency increased compulsive-like behavior on both backgrounds and PF consumption was greater with paternal inheritance. Gene expression in the hypothalamus revealed a paternal effect of Cyfip1 deletion on transcription of Cyfip1 but not Cyfip2 or Magel2. To summarize, the selective increased compulsive-like behavior and PF consumption in paternally deleted Cyfip1 +/-mice could translate to enhancing hyperphagia in a subset of individuals with neurodevelopmental disorders involving reduced expression or haploinsufficiency of CYFIP1, including PWS but also Fragile X Syndrome and 15q11.2 Microdeletion Syndrome. 3
... Vor Kurzem zeigte der Look-up der besten (niedrigster p-Wert) 1000 GWAS-SNPs für AN (kein genomweit signifikanter SNP in der zugrunde liegenden Studie) [8] in der GWAMA zum BMI [34] drei genomische Regionen, die für beide relevant zu sein scheinen. Ein Locus auf Chromosom 10 mutet besonders interessant an, da die Assoziation mit Untergewicht vor allem bei Frauen beobachtet wurde [28]. Ein Look-up der 74 mit dem Bildungsabschluss assoziierten SNPs (siehe oben) ergab für zwei eine Assoziation mit einem niedrigeren und für einen eine Assoziation mit einem höheren BMI [38]. ...
Zusammenfassung
Hintergrund
Durch molekulargenetische Analysen wurde eine kleine Anzahl von Hauptgenen identifiziert, die Übergewicht ( Body Mass Index , BMI ≥ 25 kg/m ² ) und Adipositas (BMI ≥ 30 kg/m ² ) bei Menschen mit bedingen können. Die zugrunde liegenden Mutationen sind selten. Die genetische Prädisposition zur Entwicklung einer Adipositas ist meist polygener Natur.
Ziel der Arbeit
Darstellung der polygenen Formen der Adipositas und epigenetischer Befunde.
Material und Methoden
Literaturübersicht.
Ergebnisse und Diskussion
Metaanalysen genomweiter Assoziationsstudien (GWAMA) haben bisher mehr als 100 Polygene oder polygene Loci identifiziert, die genomweit mit dem BMI assoziiert sind. Jedes einzelne Polygen leistet nur einen kleinen Beitrag zur Entwicklung einer Adipositas. Effektstärken liegen im Bereich von ca. 100 g bis 1,5 kg. Eine Reihe solcher prädisponierenden Genvarianten (Allele) findet sich bei adipösen Probanden. Allerdings tragen auch normalgewichtige und schlanke Individuen diese Allele, wenn auch in geringerer Frequenz. Diese Allele können durch statistische Analysen als Adipositas-Risikoallele identifiziert und validiert werden. Vor Kurzem haben sogenannte Cross-Disorder- und Cross-Phänotyp-Analysen zur Identifizierung von Genen geführt, die nicht allein durch Analysen der einzelnen Erkrankungen/Phänotypen nachgewiesen werden konnten. Funktionelle in-vitro - und in-vivo -Studien der GWAS-abgeleiteten Polygene könnten zu einem besseren Verständnis der molekulargenetischen Mechanismen der Körpergewichtsregulation führen. Erste genomweite Methylierungsmusteranalysen und Studien zu metastabilen Epiallelen tragen zudem zu einem besseren Verständnis der Pathomechanismen der Adipositas bei.
Objective:
Evidence linking childhood body mass index (BMI) with subsequent eating disorders is equivocal. Potential explanations include different study populations and size, and that anorexia nervosa (AN) and bulimia nervosa (BN) should be studied separately. We examined whether birthweight and childhood BMI were associated with subsequent risk of AN and BN in girls.
Method:
We included 68,793 girls from the Copenhagen School Health Records Register born between 1960 and 1996 with information on birthweight and measured weights and heights obtained from school health examinations at ages 6-15 years. Diagnoses of AN and BN were retrieved from Danish nationwide patient registers. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
Results:
We identified 355 cases of AN (median age: 19.0) and 273 cases of BN (median age: 21.8). Higher childhood BMI was linearly associated with decreasing risk of AN and increasing risk of BN at all childhood ages. At age 6, the HR for AN was 0.85 (95% CI: 0.74-0.97) per BMI z-score and the HR for BN was 1.78 (95% CI: 1.50-2.11) per BMI z-score. Birthweight >3.75 kg was associated with increased risk of BN compared to a birthweight of 3.26-3.75 kg.
Conclusion:
Higher BMI in girls at ages 6-15 years was associated with decreasing risk of AN and increasing risk of BN. Premorbid BMI could be relevant for the etiology of AN and BN, and in identifying high risk individuals.
Public significance:
Eating disorders are associated with elevated mortality, especially AN. Using a cohort of Copenhagen school children, we linked information on BMI at ages 6-15 years for 68,793 girls with nationwide patient registers. Low childhood BMI was associated with increased risk of AN, whereas high childhood BMI was associated with increased risk of BN. These findings may assist clinicians in identifying individuals at high-risk of these diseases.
La thérapie multifamiliale (TMF) consiste à regrouper dans un but thérapeutique plusieurs familles autour d'un problème commun. Développée initialement pour les troubles psychotiques, puis pour d'autres troubles psychiatriques (dont les troubles des conduites alimentaires) et certaines affections somatiques, elle a également été appliquée aux difficultés relationnelles familiales, aux problèmes scolaires et à l'exclusion sociale.
Réunissant une équipe d'auteurs français et internationaux, experts dans cette approche thérapeutique, l'ouvrage expose:
- différents modèles d'application aux TCA de l'enfant, de l'adolescent et de l'adulte
- les différentes étapes d'un programme de TMF, depuis sa conceptualisation à sa mise en place et sa pérennisation
- le cadre, les techniques et les outils qui permettent sa mise en oeuvre effective.
Tout en rappelant les fondements théoriques et les données probantes de cette modalité thérapeutique, l'ouvrage propose des outils pratiques et de nombreux exemples cliniques pour guider les thérapeutes et les équipes de soins.
Eating disorders such as anorexia nervosa, bulimia nervosa, and binge-eating disorder, have a deep social impact, concluding in death in cases of severe disease. Eating disorders affect up to 5% of the population in industrialized countries, but probably the phenomenon is under-detection and under-diagnosis. Eating disorders are multifactorial disorders, resulting from the interaction between environmental triggers, and psychological factors, but there is also a strong genetic component. In fact, genetic factors predispose approximately 33-84% to anorexia nervosa, 28-83% to bulimia nervosa, and 41-57% to binge eating disorder. Twins and family studies have provided unassailable proof of the heritability of these disorders. Other types of genetic studies, including genome-wide association studies, whole genome sequencing, and linkage analysis, allowed us to identify the genes and their variants associated with eating disorders and moreover global collaborative efforts have led to delineating the etiology of these disorders. Next Generation Sequencing technologies can be considered an ideal diagnostic approach to identify not only the common variants, such as single nucleotide polymorphism but also rare variants. Here we summarize the present knowledge on the molecular etiology and genetic determinants of eating disorders including serotonergic genes, dopaminergic genes, opioid genes, appetite regulation genes, endocannabinoid genes, and vitamin D3.
Anorexia nervosa has one of the highest death rates of all mental illnesses and one of the poorest treatment outcomes. However, one novel treatment, the neurobiologically-based treatment Temperament Based Therapy with Support (TBT-S), works with clients' temperament and traits to motivate change, ultimately managing and reducing symptoms. This practical and accessible book is the first guide to delivering TBT-S that addresses the underlying traits leading to symptoms of anorexia nervosa and helps people to manage symptoms long-term. It offers background information on the role of temperament in anorexia nervosa, the development of the TBT-S protocol and the evidence gathered. Chapters also cover how to use this therapy to augment existing treatment. A valuable resource for clinicians involved in the treatment of anorexia nervosa, including psychologists, psychiatrists, psychotherapists, specialist nurses, dieticians, and educators.
Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the interaction between genetic predisposition and environmental factors. Polygenic variants are frequent and confer small effect sizes. Rare monogenic obesity syndromes are caused by defined pathogenic variants in single genes with large effect sizes. Most of these genes are involved in the central nervous regulation of body weight; for example, genes of the leptin-melanocortin pathway. Clinically, patients with monogenic obesity present with impaired satiety, hyperphagia and pronounced food-seeking behaviour in early childhood, which leads to severe early-onset obesity. With the advent of novel pharmacological treatment options emerging for monogenic obesity syndromes that target the central melanocortin pathway, genetic testing is recommended for patients with rapid weight gain in infancy and additional clinical suggestive features. Likewise, patients with obesity associated with hypothalamic damage or other forms of syndromic obesity involving energy regulatory circuits could benefit from these novel pharmacological treatment options. Early identification of patients affected by syndromic obesity will lead to appropriate treatment, thereby preventing the development of obesity sequelae, avoiding failure of conservative treatment approaches and alleviating stigmatization of patients and their families.
Anorexia nervosa (AN) is a complex disorder with a strong genetic component. Comorbidities are frequent and there is substantial overlap with other disorders. The lack of understanding of the molecular and neuroanatomical causes has made it difficult to develop effective treatments and it is often difficult to treat in clinical practice. Recent advances in genetics have changed our understanding of polygenic diseases, increasing the possibility of understanding better how molecular pathways are intertwined. This review synthetizes the current state of genetic research providing an overview of genome-wide association studies (GWAS) findings in AN as well as overlap with other disorders, traits, pathways, and imaging results. This paper also discusses the different putative global pathways that are contributing to the disease including the evidence for metabolic and psychiatric origin of the disease.
Obesity is reaching endemic state and has a major impact on health and economy. In most cases obesity is caused by life style factors. However, the risk of becoming obese differs highly between people. Individual differences in life style, genetic, and neuroendocrine factors play a role in satiety, hunger and regulation of body weight. In a small percentage of children and adults with obesity, an underlying hormonal or genetic cause can be found. The aim of this review is to present and compare data on the extreme ends of the obesity and undernutrition spectrum in patients with Prader-Willi syndrome (PWS), Bardet-Biedl syndrome (BBS), acquired hypothalamic obesity in craniopharyngioma patients, and anorexia nervosa. This may give more insight in the role of neuroendocrine factors and might give direction for future research in conditions of severe obesity and underweight.
Anorexia nervosa (AN) is a severe eating disorder and often associated with altered humoral immune responses. However, distinct B cell maturation stages in peripheral blood in adolescents with AN have not been characterized. Treatment effects and the relationship between clinical and B cell parameters are also not fully understood. Here we investigated the phenotype of circulating B cell subsets and the relationship with body composition in adolescents with AN before (T0, n = 24) and after 6 weeks (T1, n = 20) of treatment. Using multi-parameter flow cytometry, we found increased percentages of antigen-experienced B cells and plasmablasts in patients with AN compared to healthy controls (n = 20). In contrast, percentages of CD1d ⁺ CD5 ⁺ B cells and transitional B cells with immunoregulatory roles were reduced at T0 and T1. These B cell frequencies correlated positively with fat mass, fat mass index (FMI), free fat mass index, and body mass index standard deviation score. In addition, scavenger-like receptor CD5 expression levels were downregulated on transitional B cells and correlated with fat mass and FMI in AN. Our findings that regulatory B cell subgroups were reduced in AN and their strong relationship with body composition parameters point toward an impact of immunoregulatory B cells in the pathogenesis of AN.
Polygenic factors are relevant for the genetic predispositions to the eating disorder anorexia nervosa (AN). The most recent genome-wide association study (GWAS) for AN comprised almost 17,000 patients with AN and controls. A total of eight genome-wide significant polygenic loci associated with AN have been identified. Each single polygenic locus makes only a small contribution to the development of AN. Analyses across different traits successfully identified regions/genes for AN that had not been detected by analyses of the single traits. Functional studies of the genes derived by GWAS studies aim to improve the understanding of the biological mechanisms involved in eating disorders. Epigenetic studies have not yet successfully contributed to the understanding of AN.
Alzheimer's disease (ad) is a devastating neurological disorder characterized by changes in cell-type proportions and consequently marked alterations of the transcriptome. Here we use a data-driven systems biology meta-analytical approach across three human ad cohorts, encompassing six cortical brain regions, and integrate with multi-scale datasets comprising of DNA methylation, histone acetylation, transcriptome- and genome-wide association studies, and quantitative trait loci to further characterize the genetic architecture of ad. We perform co-expression network analysis across more than twelve hundred human brain samples, identifying robust ad-associated dysregulation of the transcriptome, unaltered in normal human aging. We assess the cell-type specificity of ad gene co-expression changes and estimate cell-type proportion changes in human ad by integrating co-expression modules with single-cell transcriptome data generated from 27 321 nuclei from human postmortem prefrontal cortical tissue. We also show that genetic variants of ad are enriched in a microglial ad-associated module and identify key transcription factors regulating co-expressed modules. Additionally, we validate our results in multiple published human ad gene expression datasets, which can be easily accessed using our online resource (https://swaruplab.bio.uci.edu/consensusAD).
Diabetes mellitus ist bei jungen Frauen im Alter zwischen 15 und 25 Jahren vergleichsweise selten. Man muss von einer Punktprävalenz von < 0,2 % ausgehen. Die klinische Häufigkeit des gemeinsamen Auftretens von AN und Diabetes mellitus ist dennoch vergleichsweise hoch, so dass mutmaßlich eine überzufällige Häufigkeit des gemeinsamen Auftretens besteht. Allerdings fehlen zur AN exakte epidemiologische Daten. Gestörtes Essverhalten, das noch nicht den diagnostischen Kriterien der AN oder BN genügt, findet sich dagegen mit überzufälliger Wahrscheinlichkeit bei jungen weiblichen Typ-I-Diabetikerinnen (51). Ein Drittel der jungen Frauen mit insulinabhängigem Diabetes zeigt gestörtes Essverhalten, mehr als 10 % zeigen eine deutliche Unterdosierung oder ein Auslassen von Insulingaben zur Gewichtskontrolle.Dies erfordert insbesondere bei jüngeren Patienten eine enge Abstimmung der Therapie mit Daibetologen und Pädiatern. Gestörtes Essverhalten ist mit einer schlechteren Diabetes-Einstellung verbunden (52). In einer Metaanalyse zur Komorbidität von Diabetes mellitus und Essstörungen lässt sich bei Diabetikerinnen eine Erhöhung der Prävalenz für die Bulimia nervosa nicht aber für die Anorexia nervosa belegen.
Bei der AN kommt es durch Einschränkung oder unzureichende Steigerung der Energieaufnahme (bei Wachstum/intensivem Sport) zur Enstehung oder Aufrechterhaltung eines Untergewichts. Das Körpergewicht liegt unter dem für Geschlecht, Größe und Alter zu erwartenden Gewicht. Betroffene haben trotz ihres Untergewichts Angst davor, zu dick zu sein und/oder zu dick zu werden. Es kann jedoch sein, dass diese Angst nicht berichtet bzw. nicht bewusst wahrgenommen wird. Der ganze Körper oder einzelne Körperteile werden trotz Untergewichts als „zu dick“ empfunden (Körperbildstörung). Das Selbstwerterleben ist bei den meisten Patientinnen in hohem Maße von Figur und Körpergewicht abhängig, bei anderen steht eine Kontrolle des Gewichts für ein Gelingen einer ausreichenden Selbstkontrolle.
Nutritional science studies the relationship between food ingestion and health. The skin is among the organs that can show distinctive manifestations of nutritional excess or deficiency. Protein‐energy malnutrition, now termed severe acute malnutrition, is the most prevalent nutritional disease worldwide. Infections, including HIV, and a background of deprivation are implicated. In developing countries, malnutrition is observed mainly due to insufficient quantity of food whereas in industrialized countries it is related to an inappropriate diet. Other causes include metabolic alterations, intestinal malabsorption, congenital malformations interfering with food intake or digestion, systemic diseases such as acquired immune deficiency syndrome and malignancy, anorexia nervosa, diets for treatment of disease, allergic disorders and child neglect.
The hypothalamus contains integrative systems that support life, including physiological processes such as food intake, energy expenditure and reproduction. Here, we show that anorexia nervosa patients, contrary to normal weight and constitutionally lean individuals, respond with a paradoxical reduction in hypothalamic levels of glutamate/glutamine (Glx) upon feeding. This reversal of the Glx response is associated with decreased wiring in the arcuate nucleus and increased connectivity in the lateral hypothalamic area, which are involved in the regulation on a variety of physiological and behavioral functions including the control of food intake and energy balance. The identification of distinct hypothalamic neurochemical dysfunctions and associated structural variations in anorexia nervosa paves the way for the development of new diagnostic and treatment strategies in conditions associated with abnormal body mass index and a maladaptive response to negative energy balance.
Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality and, to a large extent, unknown pathophysiology. Structural brain differences, such as global or focal reductions in grey or white matter volumes, as well as enlargement of the sulci and the ventricles, have repeatedly been observed in individuals with AN. However, many of the documented aberrances normalize with weight recovery, even though some studies show enduring changes. To further explore whether AN is associated with neuronal damage, we analysed the levels of neurofilament light chain (NfL), a marker reflecting ongoing neuronal injury, in plasma samples from females with AN, females recovered from AN (AN-REC) and normal-weight age-matched female controls (CTRLS). We detected significantly increased plasma levels of NfL in AN vs CTRLS (medianAN = 15.6 pg/ml, IQRAN = 12.1–21.3, medianCTRL = 9.3 pg/ml, IQRCTRL = 6.4–12.9, and p < 0.0001), AN vs AN-REC (medianAN-REC = 11.1 pg/ml, IQRAN-REC = 8.6–15.5, and p < 0.0001), and AN-REC vs CTRLS (p = 0.004). The plasma levels of NfL are negatively associated with BMI overall samples (β (±se) = −0.62 ± 0.087 and p = 6.9‧10−12). This indicates that AN is associated with neuronal damage that partially normalizes with weight recovery. Further studies are needed to determine which brain areas are affected, and potential long-term sequelae.
Binge eating (BE) is a heritable trait associated with eating disorders and involves episodes of rapid, large amounts of food consumption. We previously identified cytoplasmic FMR1-interacting protein 2 (Cyfip2) as a genetic factor underlying compulsive-like BE in mice. CYFIP2 is a homolog of CYFIP1 which is one of four paternally-deleted genes in patients with Type I Prader-Willi Syndrome (PWS), a neurodevelopmental disorder whereby 70% of cases involve paternal 15q11-q13 deletion. PWS symptoms include hyperphagia, obesity (if untreated), cognitive deficits, and obsessive-compulsive behaviors. We tested whether Cyfip1 haploinsufficiency (+/-) would enhance compulsive-like behavior and palatable food (PF) intake in a parental origin- and sex-dependent manner on two Cyfip2 genetic backgrounds, including the BE-prone C57BL/6N (Cyfip2N/N) background and the BE-resistant C57BL/6J (Cyfip2J/J) background. Cyfip1+/- mice showed increased compulsive-like behavior on both backgrounds and increased PF intake on the Cyfip2N/N background. In contrast, maternal Cyfip1 haploinsufficiency on the BE-resistant Cyfip2J/J background induced a robust escalation in PF intake in wild-type Cyfip1J/J males while having no effect in Cyfip1J/- males. Notably, induction of behavioral phenotypes in wild-type males following maternal Fmr1+/- has previously been reported. In the hypothalamus, there was a paternally-enhanced reduction in CYFIP1 protein whereas in the nucleus accumbens, there was a maternally-enhanced reduction in CYFIP1 protein. No change in FMR1 protein (FMRP) was observed in Cyfip1+/- mice, regardless of parental origin. To summarize, Cyfip1 haploinsufficiency increased compulsive-like behavior and induced genetic background-dependent, sex-dependent, and parent-of-origin-dependent effects on PF consumption and CYFIP1 expression that could have relevance for neurodevelopmental and neuropsychiatric disorders.
Background:
Anorexia nervosa is a complex neuropsychiatric disorder presenting with life-threatening low body weight, and a persistent fear of gaining weight. To date, no whole exome sequencing was performed in male individuals with anorexia nervosa.
Aim and methods:
Here, we performed an exome analysis in two independent families with male individuals with anorexia nervosa and found variants in the Neuronatin (NNAT) gene in both probands. To confirm our data, we carried out the screening of the NNAT gene in a cohort of 8 male and 144 female individuals with anorexia nervosa.
Results:
Exome sequencing revealed a nonsense variant p.Trp33* in NNAT in one patient and a rare variant in the 5'UTR region of NNAT in the other patient. Screening of the NNAT gene in a cohort of 8 male and 144 female individuals with anorexia nervosa allowed to identify 11 other NNAT variants showing that 40.00% and 6.25% of male and female anorexia nervosa individuals carried a NNAT variant, respectively. Moreover, two novel missense variants were identified in female anorexia nervosa patients.
Conclusion:
Our data suggest that NNAT variants and NNAT expression changes may be associated with susceptibility to eating disorders such as anorexia nervosa.
Body image disturbance is widely viewed as contributing to the development and maintenance of disordered eating. Yet this perspective is not inconsistent with the possibility that elevated premorbid BMIs also increase the risk of developing eating disorders. Research examining whether actual body size may play a role in eating disorder development reveals a curious pattern of findings. Few prospective risk factor studies conducted with community‐based samples found a relationship between premorbid BMI and subsequent eating disorder pathology whereas retrospective research conducted with clinical samples indicates a consistent pattern of elevated premorbid BMIs relative to population norms or control groups. This study documents these disparate findings, considers potential explanations for them and proposes further study of premorbid BMI as a factor contributing to the psychopathology of eating disorders, particularly among those who come to the attention of treatment providers.
A small number of single gene mutations causing human obesity have been identified by molecular genetic analyses; the responsible mutations are rare. The genetic mechanisms involved in the predisposition to obesity in most affected people are polygenic (Locke et al., Nature 518:197–206, 2015). Currently, more than 100 such “polygenes” or “polygenic loci” harboring genetic variants associated with BMI have been identified (Yazdi et al., PeerJ 3:e856, 2015). Each single polygene makes only a small contribution, in the magnitude of a few hundred grams or less, to the development of obesity. A number of such predisposing gene variants (alleles) are found in obese subjects; however, the same alleles, although at a lower frequency, are also found in normal-weight and even lean individuals (Hebebrand et al., Dtsch Arztebl Int. 110:338–44, 2013). Evidently, these alleles can only be identified and validated as obesity-risk alleles by statistical analyses (Locke et al., Nature 518:197–206, 2015). Currently, combined genome-wide association studies (GWAS) on more than 300,000 population-based individuals have been conducted, and meta-analyses of additional GWAS (GWAMA) are under way, which will be based on over 1,000,000 mainly epidemiologically ascertained subjects. Recently, cross-disorder and cross-phenotype analyses have led to the identification of genes that had not been detected by analyses of single disorders/phenotypes alone (Hinney et al., Mol Psychiatry 22:192–201, 2017; Bulik-Sullivan et al., Nat Genet 47:1236–41, 2015). Functional in vitro and in vivo studies of the GWAS-derived polygenes are assumed to lead to a better understanding of the molecular genetic mechanisms involved in body weight regulation. It is a matter of debate if epigenetic markers can be transmitted across generations and can thus explain part of the heritability. Initial genome-wide methylation pattern analyses (Dick et al., Lancet. 383:1990–82014, 2014) and studies on “metastable epialleles” (Kühnen et al., Cell Metab. 24:502-9, 2016) pave the way to a better understanding of epigenetic mechanisms in obesity.
Objective:
Previous studies evaluating the association between early childhood adversities and eating disorders have yielded conflicting results. The aim of this study is to examine the association between a range of adversities and risk of anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS) in 495,244 women.
Method:
In this nationwide, register-based cohort study, nine types of early childhood adversity (family disruption, residential instability, placement in out-of-home care, familial death, parental somatic illness, parental psychiatric illness, parental disability, severe parental criminality, and parental substance use disorder) were defined and exposure during the first 6 years of life was determined. Hazard ratios for eating disorders were calculated using Cox regression.
Results:
Few adversities were significantly associated with AN, and for each, the presence of the adversity was associated with lower risk for AN. BN, and EDNOS were positively associated with several types of adversities. AN rates were unchanged or reduced by up to 54% by adversities, whereas rates of BN and EDNOS were unchanged or increased by adversities by up to 49 and 89%, respectively.
Discussion:
Our findings indicate that childhood adversities appear to be associated with an increased risk of BN and in particular EDNOS, whereas they seem to be either unassociated or associated with a decreased risk of AN.
The G protein-coupled receptor 83 (Gpr83) is widely expressed in brain regions regulating energy metabolism. Here we report that hypothalamic expression of Gpr83 is regulated in response to nutrient availability and is decreased in obese mice compared with lean mice. In the arcuate nucleus, Gpr83 colocalizes with the ghrelin receptor (Ghsr1a) and the agouti-related protein. In vitro analyses show heterodimerization of Gpr83 with Ghsr1a diminishes activation of Ghsr1a by acyl-ghrelin. The orexigenic and adipogenic effect of ghrelin is accordingly potentiated in Gpr83-deficient mice. Interestingly, Gpr83 knock-out mice have normal body weight and glucose tolerance when fed a regular chow diet, but are protected from obesity and glucose intolerance when challenged with a high-fat diet, despite hyperphagia and increased hypothalamic expression of agouti-related protein, Npy, Hcrt and Ghsr1a. Together, our data suggest that Gpr83 modulates ghrelin action but also indicate that Gpr83 regulates systemic metabolism through other ghrelin-independent pathways.
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, men >50y, women 50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed signifi- cant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (!50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analy- sis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimor- phism of body shape.
In addition to the identification of mutations clearly related to Mendelian forms of obesity; genome-wide association studies and follow-up studies have in the last years pinpointed several loci associated with BMI. These genetic alterations are located in or near genes expressed in the hypothalamus that are involved in the regulation of eating behavior. Accordingly, it seems plausible that these SNPs, or others located in related genes, could also help develop aberrant conduct patterns that favor the establishment of eating disorders should other susceptibility factors or personality dimensions be present. However, and somewhat surprisingly, with few exceptions such as BDNF, the great majority of the genes governing these pathways remain untested in patients with anorexia nervosa, bulimia nervosa or binge-eating disorder. In the present work, we review the few existing studies, but also indications and biological concepts that point to these genes in the CNS as good candidates for association studies with eating disorder patients.
Brain-derived neurotrophic factor (BDNF) is a key regulator of energy balance; however, its underlying mechanism remains unknown. By analyzing BDNF-expressing neurons in paraventricular hypothalamus (PVH), we have uncovered neural circuits that control energy balance. The Bdnf gene in the PVH was mostly expressed in previously undefined neurons, and its deletion caused hyperphagia, reduced locomotor activity, impaired thermogenesis, and severe obesity. Hyperphagia and reduced locomotor activity were associated with Bdnf deletion in anterior PVH, whereas BDNF neurons in medial and posterior PVH drive thermogenesis by projecting to spinal cord and forming polysynaptic connections to brown adipose tissues. Furthermore, BDNF expression in the PVH was increased in response to cold exposure, and its ablation caused atrophy of sympathetic preganglionic neurons. Thus, BDNF neurons in anterior PVH control energy intake and locomotor activity, whereas those in medial and posterior PVH promote thermogenesis by releasing BDNF into spinal cord to boost sympathetic outflow.
Copyright © 2015 Elsevier Inc. All rights reserved.
The elucidation of the molecular mechanism of adipocyte differentiation in mesenchymal stem cells is of essential importance for the development of treatments for metabolic diseases, such as obesity and diabetes.
The expression levels of miR-342-3p and carboxy-terminal binding protein 2 (CtBP2) were regulated by oligonucleotide transfection. Adipogenic differentiation was induced by adipogenic medium containing indomethacin, dexamethasone and 3-isobutyl-1-methylxanthine on day 12, as determined by Oil Red O staining and triglyceride concentration assay to assess intracellular lipid accumulation. The induction of adipocyte-specific transcription factors and markers was detected by qRT-PCR and western blot. The regulation of CtBP2 expression by miR-342-3p was determined by western blot, qRT-PCR, luciferase reporter assay, ChIP assay and functional experiments.
We revealed that miR-342-3p was enriched in the adipose tissue of obese mice, and its expression was significantly elevated during adipogenic differentiation in both human mesenchymal stem cells (hMSCs) and 3T3L1 cells. Using gain- and loss-of-function assays, we demonstrated that the overexpression of miR-342-3p markedly promoted the differentiation of hMSCs into an adipogenic lineage. Adipogenesis was significantly blocked by miR-342-3p downregulation. We identified and validated that CtBP2 was a direct target of miR-342-3p in this process. The effects of the inhibition of CtBP2 were similar to those of miR-342-5p overexpression on adipogenic differentiation, promoting the release of C/EBPα from CtBP2 binding.
miR-342-3p is a powerful enhancer of the adipogenesis of human adipose-derived MSCs that acts by inhibiting CtBP2 and releasing the key adipogenic regulator C/EBPα from CtBP2 binding, subsequently activating the expression of adipogenic transcription factors and markers. © 2015 S. Karger AG, Basel.
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for approximately 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis
Obesity is a major public health concern. This condition results from a constant and complex interplay between predisposing genes and environmental stimuli. Current attempts to manage obesity have been moderately effective and a better understanding of the etiology of obesity is required for the development of more successful and personalized prevention and treatment options. To that effect, mouse models have been an essential tool in expanding our understanding of obesity, due to the availability of their complete genome sequence, genetically identified and defined strains, various tools for genetic manipulation and the accessibility of target tissues for obesity that are not easily attainable from humans. Our knowledge of monogenic obesity in humans greatly benefited from the mouse obesity genetics field. Genes underlying highly penetrant forms of monogenic obesity are part of the leptin-melanocortin pathway in the hypothalamus. Recently, hypothesis-generating genome-wide association studies for polygenic obesity traits in humans have led to the identification of 119 common gene variants with modest effect, most of them having an unknown function. These discoveries have led to novel animal models and have illuminated new biologic pathways. Integrated mouse-human genetic approaches have firmly established new obesity candidate genes. Innovative strategies recently developed by scientists are described in this review to accelerate the identification of causal genes and deepen our understanding of obesity etiology. An exhaustive dissection of the molecular roots of obesity may ultimately help to tackle the growing obesity epidemic worldwide.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis
Heritability of obesity and body weight variation is high. Molecular genetic studies have led to the identification of mutations in a few genes, with a major effect on obesity (major genes and monogenic forms). Analyses of these genes has helped to unravel important pathways and has created a more profound understanding of body weight regulation. For most individuals, a polygenic basis is relevant for the genetic predisposition to obesity. Small effect sizes are conveyed by the polygenic variants. Hence, only if a number of these variants is harboured, a sizeable phenotypic effect is detectable. Most, if not all, of the genes relevant to weight regulation are expressed in the hypothalamus. This underscores the major role of this region of the brain in body weight regulation.
Background. Prostate cancer (PCa) racial disparity is multifactorial, involving biological, sociocultural, and lifestyle determinants. We investigated the association between selected potentially functional polymorphisms (SNPs) and prostate cancer (PCa) risk in Black (AAM) and White (EAM) men. We further explored if these associations varied by the body mass index (BMI) and height. Methods. Age-matched DNA samples from 259 AAM and 269 EAM were genotyped for 10 candidate SNPs in 7 genes using the TaqMan allelic differentiation analysis. The dominant, recessive, and additive age-adjusted unconditional logistic regression models were fitted. Results. Three SNPs showed statistically significant associations with PCa risk: in AAM, HNF1B rs7501939 (OR = 2.42, P = 0.0046) and rs4430796 (OR = 0.57, P = 0.0383); in EAM, CTBP2 rs4962416 (OR = 1.52, P = 0.0384). In addition, high BMI in AAM (OR = 1.06, P = 0.022) and height in EAM (OR = 0.92, P = 0.0434) showed significant associations. Interestingly, HNF1B rs7501939 was associated with PCa exclusively in obese AAM (OR = 2.14, P = 0.0103). Conclusion. Our results suggest that variation in the HNF1B may influence PCa risk in obese AAM.
The brain-derived neurotrophic factor (BDNF) gene may influence eating behavior, body weight and cognitive impairments. We aimed to investigate whether BDNF genetic variability may affect anthropometric and psychological parameters in patients with anorexia or bulimia nervosa (AN, BN) and/or modulate the risk for the disorder. A total of 169 unrelated female patients and 312 healthy controls were genotyped for two common BDNF single-nucleotide polymorphisms (SNPs), Val66Met and C-270T, and several selected tag-SNPs. Associated personality characteristics and psychopathological symptoms were assessed by the EDI-2 and SCL-90R inventories, respectively. No single SNP or haplotype played a relevant role in the risk for AN or BN. The rs16917237 TT genotype was significantly associated with increased weight (74.63 ± 16.58 vs. 57.93 ± 13.02) and body mass index (28.94 ± 6.22 vs. 22.23 ± 4.77) in the BN group after correcting for multiple testing. Haplotype analyses using a sliding window approach with three adjacent SNPs produced four loci of interest. Locus 3 (rs10835210/rs16917237/C-270T) showed a broad impact on the measured psychopathological symptoms. Haplotypes CGC and CGT in this locus correlated with scores in all three scales of the SCL-90R inventory, both in AN and BN patients. In contrast, the results of the EDI-2 inventory were largely unaffected. These preliminary results suggest that variability in the BDNF gene locus may contribute to anthropometric characteristics and also psychopathological symptoms that are common but not exclusive of ED patients.
Recent genetic association studies have made progress in uncovering components of the genetic architecture of the body mass index (BMI). We used the ITMAT-Broad-Candidate Gene Association Resource (CARe) (IBC) array comprising up to 49 320 single nucleotide polymorphisms (SNPs) across ∼2100 metabolic and cardiovascular-related loci to genotype up to 108 912 individuals of European ancestry (EA), African-Americans, Hispanics and East Asians, from 46 studies, to provide additional insight into SNPs underpinning BMI. We used a five-phase study design: Phase I focused on meta-analysis of EA studies providing individual level genotype data; Phase II performed a replication of cohorts providing summary level EA data; Phase III meta-analyzed results from the first two phases; associated SNPs from Phase III were used for replication in Phase IV; finally in Phase V, a multi-ethnic meta-analysis of all samples from four ethnicities was performed. At an array-wide significance (P < 2.40E-06), we identify novel BMI associations in loci translocase of outer mitochondrial membrane 40 homolog (yeast) - apolipoprotein E - apolipoprotein C-I (TOMM40-APOE-APOC1) (rs2075650, P = 2.95E-10), sterol regulatory element binding transcription factor 2 (SREBF2, rs5996074, P = 9.43E-07) and neurotrophic tyrosine kinase, receptor, type 2 [NTRK2, a brain-derived neurotrophic factor (BDNF) receptor gene, rs1211166, P = 1.04E-06] in the Phase IV meta-analysis. Of 10 loci with previous evidence for BMI association represented on the IBC array, eight were replicated, with the remaining two showing nominal significance. Conditional analyses revealed two independent BMI-associated signals in BDNF and melanocortin 4 receptor (MC4R) regions. Of the 11 array-wide significant SNPs, three are associated with gene expression levels in both primary B-cells and monocytes; with rs4788099 in SH2B adaptor protein 1 (SH2B1) notably being associated with the expression of multiple genes in cis. These multi-ethnic meta-analyses expand our knowledge of BMI genetics.
Background:
Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.
Methods:
We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.
Findings:
SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.
Interpretation:
Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.
Funding:
National Institute of Mental Health.
Genetic variants responsible for susceptibility to obesity and its comorbidities among Hispanic children have not been identified. The VIVA LA FAMILIA Study was designed to genetically map childhood obesity and associated biological processes in the Hispanic population. A genome-wide association study (GWAS) entailed genotyping 1.1 million single nucleotide polymorphisms (SNPs) using the Illumina Infinium technology in 815 children. Measured genotype analysis was performed between genetic markers and obesity-related traits i.e., anthropometry, body composition, growth, metabolites, hormones, inflammation, diet, energy expenditure, substrate utilization and physical activity. Identified genome-wide significant loci: 1) corroborated genes implicated in other studies (MTNR1B, ZNF259/APOA5, XPA/FOXE1 (TTF-2), DARC, CCR3, ABO); 2) localized novel genes in plausible biological pathways (PCSK2, ARHGAP11A, CHRNA3); and 3) revealed novel genes with unknown function in obesity pathogenesis (MATK, COL4A1). Salient findings include a nonsynonymous SNP (rs1056513) in INADL (p = 1.2E-07) for weight; an intronic variant in MTNR1B associated with fasting glucose (p = 3.7E-08); variants in the APOA5-ZNF259 region associated with triglycerides (p = 2.5-4.8E-08); an intronic variant in PCSK2 associated with total antioxidants (p = 7.6E-08); a block of 23 SNPs in XPA/FOXE1 (TTF-2) associated with serum TSH (p = 5.5E-08 to 1.0E-09); a nonsynonymous SNP (p = 1.3E-21), an intronic SNP (p = 3.6E-13) in DARC identified for MCP-1; an intronic variant in ARHGAP11A associated with sleep duration (p = 5.0E-08); and, after adjusting for body weight, variants in MATK for total energy expenditure (p = 2.7E-08) and in CHRNA3 for sleeping energy expenditure (p = 6.0E-08). Unprecedented phenotyping and high-density SNP genotyping enabled localization of novel genetic loci associated with the pathophysiology of childhood obesity.
Transcription of the gene encoding Brain-Derived Neurotropic Factor (BDNF) is induced in response to a wide variety of extracellular stimuli via the activation of a complex array of transcription factors. However, to what degree individual transcription factors confer specificity upon the regulation of Bdnf is poorly understood. Previous studies have shown that members of the myocyte enhancer factor 2 (MEF2) transcription factor family bind a regulatory element upstream of Bdnf promoter I and associate with an unknown binding site in Bdnf promoter IV. Here we identify calcium-response element 1 as the MEF2 binding site in promoter IV of the Bdnf gene and determine the requirements for individual MEF2 family members in Bdnf regulation. MEF2A, MEF2C, and MEF2D are all highly expressed in embryonic rat cortical neurons; however, only the Mef2c gene encodes an MEF2 splice variant that lacks the γ repressor-domain. We find that MEF2C variants lacking the γ-domain are particularly sensitive to activation by membrane depolarization, raising the possibility that the MEF2s may differentially contribute to activity-regulated gene expression. We find that only knockdown of MEF2C significantly impairs membrane depolarization-induced expression of Bdnf exon IV. By contrast, knockdown of MEF2D significantly enhanced depolarization-induced expression of Bdnf exon I. Together, these data show that individual members of the MEF2 family of transcription factors differentially regulate the expression of Bdnf, revealing a new mechanism that may confer specificity on the induction of this biologically important gene.
The original abstract was withdrawn.
The G-protein coupled receptor 83 (GPR83) is an orphan G-protein coupled receptor (GPCRs) that is highly expressed in thymus and brain. Within the brain GPR83 expression can especially be found in hypothalamic nuclei that are known to play an important role in body weight regulation. We explore a putative role for GPR83 in energy metabolism. By doing this we demonstrate that hypothalamic expression of GPR83 is decreased in diet-induced obese (DIO) mice compared to lean mice. Additionally, hypothalamic expression is reduced following fasting and increased upon re-feeding. Via in situ hybridization it could be shown that GPR83 is co-localized with the ghrelin receptor (GHSR1a). In vitro studies could confirm GPR83/GHSR1a heterodimerization. Functional characterization of the heterodimer suggests that GPR83 leads to a reduced activation of GHSR1a by its ligand ghrelin. In agreement, studies in GPR83-knockout mice show that loss of GPR83 potentiates the effect of both, central and peripheral ghrelin treatment, on food intake and adiposity. GPR83-knockout mice have normal body weight and glucose tolerance when fed a regular chow diet. Glucose intolerance and obesity were not observed in response to high-fat diet despite relative hyperphagia. In summary, our data suggest that GPR83 acts as a modulator of ghrelin action in response to nutrient availability. In addition to these findings GPR83 seems to play a more complex role in the regulation of systemic metabolism.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
Anorexia nervosa (AN) is a psychiatric condition characterized by severe weight loss and secondary problems associated with malnutrition. AN predominantly develops in adolescence in the peripubertal period. Without early effective treatment, the course is protracted with physical, psychological and social morbidity and high mortality. Despite these effects, patients are noted to value the beliefs and behaviours that contribute to their illness rather than regarding them as problematic, which interferes with screening, prevention and early intervention. Involving the family to support interventions early in the course of the illness can produce sustained changes; however, those with a severe and/or protracted illness might require inpatient nursing support and/or outpatient psychotherapy. Prevention programmes aim to moderate the overvaluation of ‘thinness’ and body dissatisfaction as one of the proximal risk factors. The low prevalence of AN limits the ability to identify risk factors and to study the timing and sex distribution of the condition. However, genetic profiles, premorbid features, and brain structures and functions of patients with AN show similarities with other psychiatric disorders and contrast with obesity and metabolic disorders. Such studies are informing approaches to address the neuroadaptation to starvation and the other various physical and psychosocial deficits associated with AN. This Primer describes the epidemiology, diagnosis, screening and prevention, aetiology, treatment and quality of life of patients with AN.
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR
Identifying genetic correlations between complex traits and diseases can provide useful etiological insights and help prioritize likely causal relationships. The major challenges preventing estimation of genetic correlation from genome-wide association study (GWAS) data with current methods are the lack of availability of individual-level genotype data and widespread sample overlap among meta-analyses. We circumvent these difficulties by introducing a technique-cross-trait LD Score regression-for estimating genetic correlation that requires only GWAS summary statistics and is not biased by sample overlap. We use this method to estimate 276 genetic correlations among 24 traits. The results include genetic correlations between anorexia nervosa and schizophrenia, anorexia and obesity, and educational attainment and several diseases. These results highlight the power of genome-wide analyses, as there currently are no significantly associated SNPs for anorexia nervosa and only three for educational attainment.
Background:
The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism.
Scope of review:
In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery.
Major conclusions:
In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.
The core symptomatology of anorexia nervosa consists of an intertwining of primary behavioral features and cognitions with mental and physical symptoms related to starvation, which differ depending on age and stage of the disorder [5, 9]. As such, anorexia nervosa represents a true psychosomatic disorder in the sense that both soma and psyche are affected. Patients restrict their energy intake and/or increase their energy expenditure and as a consequence lose weight. At a more or less early stage of their disorder, they establish an initial contact with medical services, in most cases a pediatrician or general practitioner. In childhood and adolescence, parents or caregivers are frequently the driving force behind this initial presentation; the young patients themselves are often reluctant to seek medical help. In single cases, teachers, friends and relatives of the patient may be crucial for the initiation of help seeking behavior by persuading the patient and her caregivers to contac ...
Myostatin is a critical negative regulator of skeletal muscle development and it has been reported to be involved in the progression of obesity and diabetes. In this study, we explore the effects of myostatin on the proliferation and differentiation of 3T3-L1 preadipocytes by using MTT spectrophotometry, intracellular triglyceride assays and real-time quantitative RT-PCR methods. The results showed that recombinant myostatin significantly promoted the proliferation of 3T3-L1 preadipocytes, and the expression of proliferation related genes including cyclin B2, cyclin D1, cyclin E1, PCNA, c-Myc and IGF-1 levels in the medium of 3T3-L1 were notably up-regulated by 35.2 %, 30.5 %, 20.5 %, 33.4 %, 51.2 % and 179 % (all P<0.01) in myostatin treated 3T3-L1 cells. Meanwhile, the intracellular lipids content in myostatin treated cells were notably reduced when compared with the non-treated cells. Additionally, the mRNA levels of PPARγ, C/EBPα, GPDH, DGAT, ACS1, ATGL and HSL were significantly down-regulated by 22 % ~76 % in fully differentiated myostatin-treated adipocytes. Finally, myostatin regulated the mRNA levels and secretion of adipokines including adiponectin, resistin, visfatin and PAI-1 in 3T3-L1 adipocytes (all P<0.001). Above all, myostatin promote 3T3-L1 proliferation through increasing the expression of cell proliferation related genes and stimulating IGF-1 secretion. Myostatin inhibited 3T3-L1 adipocyte differentiation by suppressing PPARγ and C/EBPα expressions, consequently deceased lipid accumulation in 3T3-L1 cells by inhibiting the expression of critical lipogenic enzymes and promoting the expression of lipolysis enzymes. Finally, myostatin modulated the expression and secretion of adipokines in fully differentiated 3T3-L1 adipocytes.
Objective
To study recent time trends in the incidence of diagnosed anorexia nervosa (AN) and bulimia nervosa (BN) based on nationwide psychiatric register data.Method
The Danish Psychiatric Central Research Registry was used to identify the incidence of diagnosed cases with AN and BN at the ages of 4–65 years from 1995 to 2010. Age- and sex-adjusted incidence rates per 100,000 person-years were calculated and were adjusted for time trends in the total number of people diagnosed in psychiatry. Time trends were analyzed using JoinPoint regression analysis.ResultsA total of N = 5,902 persons had a first-time incidence of AN, and a total of N = 5,113 had first-time incidence of BN. Incidence rates increased for AN from 6.4 to 12.6 per 100,000 person-years, and for BN from 6.3 to 7.2 per 100,000 person-years. In 2010, the male-to-female ratio was 1:8 for AN, and 1:20 for BN. There was an earlier onset for AN than for BN, and age at incidence decreased during the observation period for AN but not for BN. A sizeable part of the increasing incidence rates for AN and in particular, the younger AN age groups, could be attributed to an increase in the total number of N = 249,607 persons with first-time diagnoses in psychiatry.DiscussionIncidence rates had increased slightly for AN, but were stable for BN across 16 years in this nationwide study and to a large extent were reflective of a general increase in diagnosed mental disorders. (Int J Eat Disord 2015)
Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.