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Ida Surakka,
John B Whitfield,
Markus Perola,
Peter M Visscher,
Grant W Montgomery,
Mario Falchi,
Gonneke Willemsen,
Eco J C de Geus,
Patrik K E Magnusson,
Kaare Christensen, [......],
Ann-Christine Syvänen,
Aarno Palotie, Jaakko Kaprio,
Kirsten O Kyvik,
Nancy L Pedersen,
Dorret I Boomsma,
Tim Spector,
Nicholas G Martin,
Samuli Ripatti,
Leena Peltonen
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ABSTRACT: Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene-environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (P = 3.98 × 10-8). We followed up the association in further genotyped monozygotic twins (N = 1,261), which showed a moderate association for the variant (P = 0.200, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (P = 4.03 × 10-8).
Twin Research and Human Genetics 10/2012; · 1.70 Impact Factor
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ABSTRACT: Noise sensitivity is considered to be a self-perceived indicator of vulnerability to stressors in general and not noise alone. Multiple chemical sensitivity (MCS) has to some extent been accompanied by noise sensitivity, indicating a moderate correspondence between them. The aim of this study is to investigate if the Weinstein's Noise Sensitivity Scale and Quick Environmental Exposure and Sensitivity Inventory's (QEESI) Chemical Intolerance Subscale can differentiate noise sensitivity and MCS as different entities, and if there are overlaps in the characteristics of noise sensitivity and MCS. In 2002, 327 individuals (166 men, 161 women; age range 45 - 66 years) from the Finnish Twin Cohort answered a questionnaire on noise-related and MCS items. Somatic, psychological, and lifestyle factors were obtained through earlier questionnaires for the same individuals. Both confirmatory and exploratory factor analyses (CFA and EFA) of the questionnaire items on the Weinstein's Noise Sensitivity Scale and QEESI's Chemical Intolerance Subscale indicated the presence of three factors - Noise Sensitivity, Chemical Sensitivity, and Ability to Concentrate factors - arising from the forming of two factors from the items of the Weinstein's scale. In the regression analyses, among all subjects, the Noise Sensitivity Factor was associated with neuroticism and smoking, and the Chemical Sensitivity Factor was associated with allergies and alcohol use. The study indicates that the Weinstein's Noise Sensitivity Scale and QEESI's Chemical Intolerance Subscale differentiate noise sensitivity and MCS as different entities.
Noise and Health 10/2012; 1460(Issue : 60-2012 | Volume : 14):215-23. · 1.25 Impact Factor
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ABSTRACT: Noise sensitivity is considered to be a self-perceived indicator of vulnerability to stressors in general and not noise alone. Multiple chemical sensitivity (MCS) has to some extent been accompanied by noise sensitivity, indicating a moderate correspondence between them. The aim of this study is to investigate if the Weinstein's Noise Sensitivity Scale and Quick Environmental Exposure and Sensitivity Inventory's (QEESI) Chemical Intolerance Subscale can differentiate noise sensitivity and MCS as different entities, and if there are overlaps in the characteristics of noise sensitivity and MCS. In 2002, 327 individuals (166 men, 161 women; age range 45 - 66 years) from the Finnish Twin Cohort answered a questionnaire on noise-related and MCS items. Somatic, psychological, and lifestyle factors were obtained through earlier questionnaires for the same individuals. Both confirmatory and exploratory factor analyses (CFA and EFA) of the questionnaire items on the Weinstein's Noise Sensitivity Scale and QEESI's Chemical Intolerance Subscale indicated the presence of three factors - Noise Sensitivity, Chemical Sensitivity, and Ability to Concentrate factors - arising from the forming of two factors from the items of the Weinstein's scale. In the regression analyses, among all subjects, the Noise Sensitivity Factor was associated with neuroticism and smoking, and the Chemical Sensitivity Factor was associated with allergies and alcohol use. The study indicates that the Weinstein's Noise Sensitivity Scale and QEESI's Chemical Intolerance Subscale differentiate noise sensitivity and MCS as different entities.
Noise and Health 10/2012; 1460(Issue 60-2012 | September-October | Volume 14 |):215-23. · 1.25 Impact Factor
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ABSTRACT: Little is known about the association of mild symptoms and mental well-being with risk of disability pension (DP) due to somatic diagnoses, even less for DP due to low back diagnoses (LBD). Moderate genetic influences on personality traits, life dissatisfaction and DP exist suggesting that shared genetic influences may underlie these associations. One can control for familial confounding (genetics and family environment) by examining twins. This twin study aimed to investigate personality traits and life dissatisfaction as predictors for DP due to LBD accounting for familial confounding.
Data on 24043 twins aged 18-65year in a baseline survey in 1975 was followed up from national DP register data until 2004. Personality traits were assessed using the short version of the Eysenck Personality Inventory and life dissatisfaction was measured with a four item scale on levels of interest, happiness, easiness, and loneliness of life. Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI).
DP due to LBD was granted to 537 individuals during the follow-up. Each one unit increase in life dissatisfaction (HR 1.06; 95%CI 1.03, 1.10) and neuroticism (1.07; 1.03, 1.10) but not extroversion was significantly associated with an elevated risk for DP due to LBD. These associations with life dissatisfaction and neuroticism remained when socioeconomic status, education, and marital status were taken into account, and demonstrated an independence from familial confounding.
Life dissatisfaction and neuroticism seems to be early, perhaps causal risk factors for DP due to LBD.
Journal of psychosomatic research 10/2012; 73(4):289-94. · 2.91 Impact Factor
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ABSTRACT: Although potential environmental influences on hedonic responses to oral pungency have been identified, little is known of the possible role of genetics underlying these responses. We explored the contribution of genetic and environmental influences on the pleasantness of oral pungency and spicy foods. Respondents were young adult Finnish twins (n=331, 21-25years), including 47 complete monozygotic and 93 dizygotic twin pairs and 51 twin individuals without their co-twin. Pleasantness and intensity of strawberry jelly spiked with capsaicin (0.0001% w/v) relative to untainted strawberry jelly were rated. Furthermore, pleasantness of spicy foods and oral pungency caused by spices were rated based on food names in a questionnaire. Respondents were grouped as non-likers, medium-likers, and likers by their pleasantness responses to capsaicin spiked jelly. The contribution of genetic and environmental factors to variation and co-variation of the pleasantness traits was analyzed using quantitative genetic modeling. The non-likers perceived oral pungency as more intense (sensory) and rated pleasantness of spicy foods and pungent sensations caused by spices (questionnaire) as less pleasant than the likers. Genetic factors accounted for 18-58% of the variation in the pleasantness of oral pungency, spicy foods and pungent sensations. The rest was due to environmental factors. All pleasantness traits (sensory and questionnaire based) were shown to share a common genetic variance. This indicates that an underlying genetic aptitude to like oral pungency, and spicy foods exists and it is expressed in these measures. The findings broaden the understanding of the diverse nature of individual food preferences and motivate further search for the underlying genetic components of oral pungency.
Physiology & Behavior 09/2012; 107(3):381-389. · 2.87 Impact Factor
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Eero Kajantie,
Kirsi H Pietiläinen,
Karoliina Wehkalampi,
Laura Kananen,
Katri Räikkönen,
Aila Rissanen,
Petteri Hovi, Jaakko Kaprio,
Sture Andersson,
Johan G Eriksson,
Iiris Hovatta
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ABSTRACT: BACKGROUND: Shorter leucocyte telomere length (LTL) is a promising marker of biological ageing. It is predicted by cumulative adverse conditions throughout life course, but few studies have data from the prenatal period when most developmental processes and cell replication take place. We studied whether body size at birth and underlying factors including severely preterm birth predict LTL in adult life. METHODS: We used data from following three cohorts: (i) 1894 subjects (age: 56-69 years) from the Helsinki Birth Cohort Study (HBCS), representing normal variation in fetal growth; (ii) the Helsinki Study of Very Low Birth Weight Adults encompassing 164 subjects born preterm at very low birthweight (<1500 g; representing extreme pre- and neonatal conditions) and 170 term-born controls (18-27 years) and (iii) 248 twins (23-31 years) from the FinnTwin16 cohort, allowing comparisons between twin pairs. Relative telomere length was measured from leucocytes by real-time quantitative polymerase chain reaction. RESULTS: Shorter LTL was associated with higher age in HBCS and among men in the Helsinki Study of Very Low Birth Weight Adults and with lower childhood socio-economic status in HBCS and FinnTwin16. LTL was not associated with weight, length or gestational age at birth in any cohort. LTL was similar in very-low-birthweight and control subjects. CONCLUSIONS: LTL is unlikely to be a useful marker of a mechanism linking body size at birth with individual differences in ageing in the general population.
International Journal of Epidemiology 09/2012; 41(5):1400-1408. · 6.41 Impact Factor
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ABSTRACT: In 1990, Blum and colleagues first reported an association between DRD2 and alcoholism. While there have been subsequent replications of this genetic association, there have also been numerous studies that failed to detect an association between DRD2 and alcohol dependence. We propose that one aspect contributing to this inconsistency is the variation in alcohol phenotype used across studies. Within the population-based Finnish twin sample, FinnTwin16, we previously performed multivariate twin analyses to extract latent genetic factors, which account for the variation across seven measures of alcohol consumption (frequency of drinking, frequency × quantity, frequency of heavy drinking, frequency of intoxication and maximum drinks in a 24-hour period) and problems (the Rutgers Alcohol Problem Index-RAPI and the Mälmö-modified Michigan Alcohol Screen Test-MmMAST) in 3065 twins. In the present study, we examined the association between 31 DRD2/ANKK1 single-nucleotide polymorphisms (SNPs) and the genetic factor scores generated by twin analyses in a subset of FinnTwin16 (n = 602). We focus on two of the genetic factors: a general alcohol consumption and problems factor score, which represents shared genetic variance across alcohol measures, and a alcohol problems genetic factor score, which loads onto the two indices of problematic drinking (MAST and RAPI). After correction for multiple testing across SNPs and phenotypes, of the 31 SNPs genotyped across DRD2/ANKK1, one SNP (rs10891549) showed significant association with the general alcohol consumption and problems factor score (P = 0.004), and four SNPs (rs10891549, rs1554929, rs6275, rs6279), representing two independent signals after accounting for linkage disequilibrium, showed significant association with the alcohol problems genetic factor score (P = 0.005, P = 0.005, P = 0.003, P = 0.003). In this study, we provide additional positive evidence for the association between DRD2/ANKK1 and alcohol outcomes, including frequency of drinking and drinking problems. Additionally, post hoc analyses indicate stronger association signals using genetic factor scores than individual measures, which suggest that accounting for the genetic architecture of the alcohol measures reduces genetic heterogeneity in alcohol dependence outcomes in this sample and enhances the ability to detect association.
Addiction Biology 09/2012; · 4.83 Impact Factor
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ABSTRACT: Objectives: The aim of the present study was to examine the role of genetic and environmental factors in the phenotypic variance of bruxism in a large population-based cohort of young adult twins in Finland. Methods: The material of the present study derives from the FinnTwin16 cohort study consisting of five birth cohorts of twin pairs born in 1975-1979 who completed a questionnaire (at mean age 24, range 23-27 years) with data on frequency of sleep-related bruxism in 2000-2002. We used quantitative genetic modeling, based on the genetic similarity of monozygotic and dizygotic twins, to estimate the most probable genetic model for bruxism, based on decomposition of phenotypic variance into components: additive genetic effects (A), dominant genetic effects (D), and non-shared environmental effects (E). Results: On average, 8.7% experienced bruxism weekly, 23.4% rarely, and 67.9% never, with no significant gender difference (p = .052). The best fitting genetic model for bruxism was the AE-model. Additive genetic effects accounted for 52% (95% CI 0.41-0.62) of the total phenotypic variance. Sex-limitation model revealed no gender differences. Conclusions: Genetic factors account for a substantial proportion of the phenotypic variation of the liability to sleep-related bruxism, with no gender difference in its genetic architecture.
Twin Research and Human Genetics 09/2012; · 1.70 Impact Factor
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Vesna Boraska,
Oliver S P Davis,
Lynn F Cherkas,
Sietske G Helder,
Juliette Harris,
Isabel Krug,
Thomas Pei-Chi Liao,
Janet Treasure,
Ioanna Ntalla,
Leila Karhunen,
Anna Keski-Rahkonen,
Danai Christakopoulou,
Anu Raevuori,
So-Youn Shin,
George V Dedoussis, Jaakko Kaprio,
Nicole Soranzo,
Tim D Spector,
David A Collier,
Eleftheria Zeggini
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ABSTRACT: Eating disorders (EDs) are common, complex psychiatric disorders thought to be caused by both genetic and environmental factors. They share many symptoms, behaviors, and personality traits, which may have overlapping heritability. The aim of the present study is to perform a genome-wide association scan (GWAS) of six ED phenotypes comprising three symptom traits from the Eating Disorders Inventory 2 [Drive for Thinness (DT), Body Dissatisfaction (BD), and Bulimia], Weight Fluctuation symptom, Breakfast Skipping behavior and Childhood Obsessive-Compulsive Personality Disorder trait (CHIRP). Investigated traits were derived from standardized self-report questionnaires completed by the TwinsUK population-based cohort. We tested 283,744 directly typed SNPs across six phenotypes of interest in the TwinsUK discovery dataset and followed-up signals from various strata using a two-stage replication strategy in two independent cohorts of European ancestry. We meta-analyzed a total of 2,698 individuals for DT, 2,680 for BD, 2,789 (821 cases/1,968 controls) for Bulimia, 1,360 (633 cases/727 controls) for Childhood Obsessive-Compulsive Personality Disorder trait, 2,773 (761 cases/2,012 controls) for Breakfast Skipping, and 2,967 (798 cases/2,169 controls) for Weight Fluctuation symptom. In this GWAS analysis of six ED-related phenotypes, we detected association of eight genetic variants with P < 10(-5) . Genetic variants that showed suggestive evidence of association were previously associated with several psychiatric disorders and ED-related phenotypes. Our study indicates that larger-scale collaborative studies will be needed to achieve the necessary power to detect loci underlying ED-related traits. © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2012; 159B(7):803-11. · 3.70 Impact Factor
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ABSTRACT: OBJECTIVE: The aim of this study was to evaluate the possibility of preventing the metabolic health consequences of postmenopausal hypogonadism with the use of long-term hormone therapy (HT). METHODS: We used a monozygotic co-twin control design including 10 twin pairs (aged 56-62 y) discordant for HT (duration of HT, 2-10 y). In addition, 14 premenopausal women (aged 29-35 y) who did not use HT were studied to evaluate the differences in metabolic health between the premenopausal and postmenopausal states. Body composition was determined, and waist-to-hip ratio was used as an estimate for fat distribution. Serum sex steroids, sex hormone-binding globulin, and serum lipid and glucose profiles were analyzed. The serum levels of adiponectin, monocyte chemotactic protein-1, and leptin, as well as their local transcript levels in adipose tissue, skeletal muscle, and leukocytes, were measured. RESULTS: Long-term HT was associated with a healthier amount and distribution of body fat. No difference was seen in serum lipid concentrations between HT users and their nonusing identical twin sisters, but fasting serum glucose and glycated hemoglobin levels were 5% and 3% lower in HT users than in nonusers, respectively. Among the adipokines analyzed, the most notable finding was a 15% lower level of monocyte chemotactic protein-1 in HT users, particularly with respect to its suggested mediator role between obesity and insulin resistance. CONCLUSIONS: Long-term HT is associated with healthier amount and distribution of body fat and better adipocytokine profile, with concomitant signs of improved insulin sensitivity.
Menopause (New York, N.Y.) 08/2012; · 3.08 Impact Factor
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Tanya M Teslovich,
Kiran Musunuru,
Albert V Smith,
Andrew C Edmondson,
Ioannis M Stylianou,
Masahiro Koseki,
James P Pirruccello,
Samuli Ripatti,
Daniel I Chasman,
Cristen J Willer, [......],
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Cornelia M van Duijn,
Leena Peltonen,
Gonçalo R Abecasis,
Michael Boehnke,
Sekar Kathiresan
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Tanya M Teslovich,
Kiran Musunuru,
Albert V Smith,
Andrew C Edmondson,
Ioannis M Stylianou,
Masahiro Koseki,
James P Pirruccello,
Samuli Ripatti,
Daniel I Chasman,
Cristen J Willer, [......],
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Cornelia M van Duijn,
Leena Peltonen,
Gonçalo R Abecasis,
Michael Boehnke,
Sekar Kathiresan
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Robert A Scott,
Vasiliki Lagou,
Ryan P Welch,
Eleanor Wheeler,
May E Montasser,
Jian'an Luan,
Reedik Mägi,
Rona J Strawbridge,
Emil Rehnberg,
Stefan Gustafsson, [......],
Nabila Bouatia-Naji,
Mark I McCarthy,
Paul W Franks,
James B Meigs,
Tanya M Teslovich,
Jose C Florez,
Claudia Langenberg,
Erik Ingelsson,
Inga Prokopenko,
Inês Barroso
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ABSTRACT: Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
Nature Genetics 08/2012; 44(9):991-1005. · 35.53 Impact Factor
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Sarah M Hartz,
Susan E Short,
Nancy L Saccone,
Robert Culverhouse,
LiShiun Chen,
Tae-Hwi Schwantes-An,
Hilary Coon,
Younghun Han,
Sarah H Stephens,
Juzhong Sun, [......],
Andrew Heath,
Eric O Johnson, Jaakko Kaprio,
Pamela Madden,
Nicholas G Martin,
Victoria L Stevens,
Jerry A Stitzel,
Robert B Weiss,
Peter Kraft,
Laura J Bierut
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ABSTRACT: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.
To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.
Primary data.
Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.
Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.
Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01).
These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
Archives of general psychiatry 08/2012; 69(8):854-60. · 12.26 Impact Factor
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ABSTRACT: We analyzed the characteristics associated with the growth in weight of Japanese triplets from birth to 12 years of age. The study included 376 mothers and their 1,128 triplet children, who were born between 1978 and 2006. Data were collected through a mailed questionnaire sent to the mothers asking for information recorded in medical records. For these births, data on triplets' weight growth, gestational age, sex, parity, maternal age at delivery, maternal height, and maternal body mass index were obtained from records in the Maternal and Child Health Handbooks and records in the school where children receive health check-ups. The weight deficit of the triplets compared to the general population of Japan remained between 10% and 17% until 12 years of age. Moreover, at 12 years of age, the differences of weight between the general population and triplets were approximately -4.75 kg for boys and -6.00 kg for girls. Very low birth weight had the strongest contribution to body weight until 8 years of age. After 8 years of age, maternal body mass index was a significant factor affecting the weight of triplets until 12 years of age.
Twin Research and Human Genetics 07/2012; 15(5):672-9. · 1.70 Impact Factor
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ABSTRACT: OBJECTIVE: To examine psychiatric comorbidity and factors that influence the outcome of bulimia nervosa (BN) in the general population. METHOD: Women from the nationwide birth cohorts of Finnish twins were screened for lifetime BN (N = 59) by using questionnaires and the Structured Clinical Interview for DSM-IV. We assessed psychiatric comorbidity and other prognostic factors. RESULTS: Among women with lifetime BN, the following were more common than among unaffected women: current major depressive disorder (p = 0.004), lifetime major depressive disorder (p = 0.00001) and heavy drinking (p = 0.01). Decreased likelihood of recovery was associated with a history of lifetime major depressive disorder (hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.23-0.84) and high drive for thinness at time of assessment (HR 0.96, 95% CI 0.93-0.99). DISCUSSION: Heavy drinking and depression present challenges for many women with BN. Major depressive disorder emerged as the only statistically significant prognostic factor of BN in this nationwide cohort; high drive for thinness was characteristic of the persistently ill. Copyright © 2012 John Wiley & Sons, Ltd and Eating Disorders Association.
European Eating Disorders Review 06/2012; · 1.38 Impact Factor
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Liana K Billings,
Yi-Hsiang Hsu,
Rachel J Ackerman,
Josée Dupuis,
Benjamin F Voight,
Laura J Rasmussen-Torvik,
Serge Hercberg,
Mark Lathrop,
Daniel Barnes,
Claudia Langenberg, [......],
Alan R Shuldiner,
Lyle J Palmer,
Nick Wareham,
Pierre Meneton,
Toby Johnson,
James S Pankow,
David Karasik,
James B Meigs,
Douglas P Kiel,
Jose C Florez
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ABSTRACT: Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in ∼19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r(2) > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post-oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations.
Diabetes 06/2012; 61(8):2176-86. · 8.29 Impact Factor
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Tobias Freilinger,
Verneri Anttila,
Boukje de Vries,
Rainer Malik,
Mikko Kallela,
Gisela M Terwindt,
Patricia Pozo-Rosich,
Bendik Winsvold,
Dale R Nyholt,
Willebrordus P J van Oosterhout, [......],
Thomas Meitinger,
Bertram Müller-Myhsok,
John-Anker Zwart,
Markus Färkkilä,
Alfons Macaya,
Michel D Ferrari,
Christian Kubisch,
Aarno Palotie,
Martin Dichgans,
Arn M J M van den Maagdenberg
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ABSTRACT: Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10(-4); combined P = 7.06 × 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 × 10(-4); combined P = 1.17 × 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10(-8) and P = 0.02; combined P = 3.86 × 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.
Nature Genetics 06/2012; 44(7):777-82. · 35.53 Impact Factor
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Alisa K Manning,
Marie-France Hivert,
Robert A Scott,
Jonna L Grimsby,
Nabila Bouatia-Naji,
Han Chen,
Denis Rybin,
Ching-Ti Liu,
Lawrence F Bielak,
Inga Prokopenko, [......],
Tatijana Zemunik,
Lina Zgaga,
Nicholas J Wareham,
Mark I McCarthy,
Ines Barroso,
Richard M Watanabe,
Jose C Florez,
Josée Dupuis,
James B Meigs,
Claudia Langenberg
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ABSTRACT: Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
Nature Genetics 05/2012; 44(6):659-69. · 35.53 Impact Factor
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ABSTRACT: Mobility decline, the coexistence of several sensory difficulties and fear of falling (FOF) are all common concerns in older people; however, knowledge about the combined effect of FOF and coexisting sensory difficulties on mobility is lacking.
Data on self-reported FOF, difficulties in hearing, vision, balance, and walking 2 km were gathered with a structured questionnaire among 434 women aged 63-76 years at baseline and after a 3-year follow-up. Logistic regression models were used for analyses.
Every third participant reported difficulties in walking 2 km at baseline. In cross-sectional analysis, the odds ratio for difficulties in walking 2 km was higher among persons who reported FOF compared with persons without FOF and the odds increased with the increasing number of sensory difficulties. Persons who reported FOF and who had three sensory difficulties had almost fivefold odds (odds ratio = 4.7, 95% confidence interval = 1.9-11.7) for walking difficulties compared with those who reported no FOF and no sensory difficulties. Among the 290 women without walking difficulties at baseline, 54 participants developed difficulty in walking 2 km during the 3-year follow-up. Odds ratio for incident walking difficulty was 3.5 (95% confidence interval = 1.6-7.8) in participants with FOF and with 2-3 sensory difficulties compared with persons without FOF and with at most one sensory difficulty at baseline.
Older women who have several coexisting sensory difficulties combined with FOF are particularly vulnerable to mobility decline. Avoidance of walking as a result of FOF is likely to be reinforced when multiple sensory difficulties hinder reception of accurate information about the environment, resulting in accelerated decline in walking ability.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 04/2012; 67(11):1230-7. · 4.60 Impact Factor
