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ABSTRACT: To summarize the advantages and limitations of general population, high-risk and "natural experiment" longitudinal studies for studying psychological change. The English and Romanian Adoptees study is used as an example of a "natural experiment," and detailed findings are provided.
What is new is a focus on the young people who spent the whole of their life in institutional care up to the time of adoption and who did not show subnutrition. The results were compared with a composite comparison group who had not experienced institutional care or who were adopted before the age of 6 months. The outcomes were assessed in terms of previously established deprivation-specific patterns (DSPs).
"Pure" psychosocial deprivation was associated with a substantial increase in the rate of DSPs. It was not associated with significantly impaired head growth if institutional care lasted less than 6 months, whereas thereafter there was a 2.5 standard deviation reduction. Subnutrition differed in being accompanied by impaired head and body growth even with institutional care lasting less than 6 months. In the pure psychosocial deprivation group, 45.5% showed a DSP at 15 years compared with 1.3% in the comparison group.
"Pure" psychosocial deprivation (in the absence of subnutrition) had a profound effect on psychological functioning in the form of DSPs. Subnutrition had a surprisingly small effect on DSPs.
Journal of the American Academy of Child and Adolescent Psychiatry 08/2012; 51(8):762-70. · 4.98 Impact Factor
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ABSTRACT: There is a debate over whether disruptive behaviour should be regarded as a central component of, or rather as an epiphenomenon with little diagnostic value for, psychopathy.
To test whether callous-unemotional traits and conduct disorder can be dissociated in the English and Romanian Adoptee Study, a prospective longitudinal study of adopted individuals with a history of severe early institutional deprivation.
The Child and Adolescent Psychiatric Assessment was used to establish DSM-IV diagnoses for conduct disorder (and also oppositional defiant disorder) at the 15-year follow-up stage. The Inventory of Callous-Unemotional Traits questionnaire was administered to assess psychopathy traits.
There was no significant association between callous-unemotional traits and conduct disorder, both according to parent and youth self-report assessed categorically and dimensionally after controlling for confounds.
The majority of individuals with high callous-unemotional traits did not show conduct disorder in this special sample of children. This supports the view that, while common, an overlap between these aspects of psychopathology is not inevitable and so provides evidence for the dissociation of these two concepts. In terms of classification, we argue for a diagnostic scheme where psychopathy can be diagnosed independently of conduct disorder.
The British journal of psychiatry: the journal of mental science 11/2011; 200(3):197-201. · 6.62 Impact Factor
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ABSTRACT: Leukocyte telomere length (LTL) is a predictor of age-related disease onset and mortality. The association in adults of psychosocial stress or stress biomarkers with LTL suggests telomere biology may represent a possible underlying mechanism linking stress and health outcomes. It is, however, unknown whether stress exposure in intrauterine life can produce variations in LTL, thereby potentially setting up a long-term trajectory for disease susceptibility. We, therefore, as a first step, tested the hypothesis that stress exposure during intrauterine life is associated with shorter telomeres in adult life after accounting for the effects of other factors on LTL. LTL was assessed in 94 healthy young adults. Forty-five subjects were offspring of mothers who had experienced a severe stressor in the index pregnancy (prenatal stress group; PSG), and 49 subjects were offspring of mothers who had a healthy, uneventful index pregnancy (comparison group; CG). Prenatal stress exposure was a significant predictor of subsequent adult telomere length in the offspring (178-bp difference between prenatal stress and CG; d = 0.41 SD units; P < 0.05). The effect was substantially unchanged after adjusting for potential confounders (subject characteristics, birth weight percentile, and early-life and concurrent stress level), and was more pronounced in women (295-bp difference; d = 0.68 SD units; P < 0.01). To the best of our knowledge, this study provides the first evidence in humans of an association between prenatal stress exposure and subsequent shorter telomere length. This observation may help shed light on an important biological pathway underlying the developmental origins of adult health and disease risk.
Proceedings of the National Academy of Sciences 08/2011; 108(33):E513-8. · 9.68 Impact Factor
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Edmund J S Sonuga-Barke, Robert Kumsta,
Wolff Schlotz,
Jessica Lasky-Su,
Rafaela Marco,
Ana Miranda,
Fernando Mulas,
Robert D Oades,
Tobias Banaschewski,
Ueli Mueller, [......],
Jan Buitelaar,
Richard Ebstein,
Michael Gill,
Richard Anney,
Herbert Roeyers,
Aribert Rothenberger,
Joseph Sergeant,
Hans Christoph Steinhausen,
Philip Asherson,
Stephen V Faraone
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ABSTRACT: Impulsive drive for immediate reward (IDIR) and delay aversion are dissociable elements of the preference for immediate over delayed rewards seen in attention-deficit/hyperactivity disorder (ADHD). We hypothesized that IDIR would be associated with dopamine regulating genes and delay aversion would be associated with serotonin-regulating genes.
Impulsive drive for immediate reward and delay aversion were measured in 459 male children and adolescents (328 ADHD and 131 unaffected siblings) with a laboratory choice task. The sample was genotyped for the 5HTT (SLC6A4) promoter serotonin-transporter-linked polymorphic region polymorphism and a DAT1 (SLC6A3) 40-base pair variable number tandem repeat located in the 3'-untranslated region of the gene.
There was no effect of dopamine transporter (DAT)1 on IDIR. As predicted, serotonin-transporter-linked polymorphic region s-allele carriers were more delay averse. This effect was driven by the s/l genotype in the ADHD group. These results were not altered by taking account of the rs25531 A/G single nucleotide polymorphism and were independent of age, IQ, and oppositional defiant disorder symptoms.
The results support the genetic distinctiveness of IDIR and delay aversion in ADHD and implicate serotonin function in delay aversion. Possible explanations of the heterosis effect in the ADHD cases are presented.
Biological psychiatry 04/2011; 70(3):230-6. · 8.93 Impact Factor
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ABSTRACT: Glucocorticoid receptor levels are thought to be controlled by multiple alternative first exons. Seven of these exons are located in an upstream CpG island. In this study, we investigated the promoter activity of the intronic regions between these exons, and their susceptibility to CpG methylation and sequence variability. The seven promoters were cloned into luciferase reporter genes, and their activity measured in ten cell lines. CpG islands of 221 donors were genotyped and the effects of these SNPs were investigated in a reporter gene assay. We showed that each of the first exons was independently controlled by a unique promoter located directly upstream. Promoter activities were cell type-specific, and varied considerably between cell types. Irrespective of the cell type, in vitro methylation effectively silenced all reporter constructs. Eleven SNPs were observed within the CpG island of 221 donors, and a new promoter-specific haplotype was revealed. Four of the minor alleles reduced the reporter gene activity, with cell type specific effects. This complexity within the CpG island helps to explain the variable, tissue-specific transcriptional control of the GR, and provides insight into the mechanisms underlying tissue specific deregulation of GR levels.
Human Genetics 01/2011; 129(5):533-43. · 5.07 Impact Factor
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Monographs of the Society for Research in Child Development 04/2010; 75(1):48-78. · 5.50 Impact Factor
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Monographs of the Society for Research in Child Development 04/2010; 75(1):79-101. · 5.50 Impact Factor
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ABSTRACT: Throughout this monograph, there has been frequent reference to levels of risk, inference of causation, testing for mediating variables, and the need to consider possible moderating influences. In this chapter, we review what is meant by these concepts, and then seek to pull together the findings from the English and Romanian Adoptee (ERA) studies that were relevant for these issues. When the findings have been presented in detail in earlier chapters, we simply summarize the main salient points. However, with respect to possible genetic moderation of the effects of institutional deprivation, we present new data because these were not considered in earlier chapters. There was a time when most developmental research, particularly that dealing with social development, moved blithely ahead using cross-sectional studies to investigate developmental processes without consideration of the multiple complex ways in which these processes may work together or separately. That is no longer acceptable (Kraemer et al., 1997; Kraemer, Stice, Kazdin, Offord, & Kupfer, 2001; Murray, Farrington, & Eisner, 2009; Rutter, 1988, 2009). Not only must the various processes, and their interplay, be clearly conceptualized, but also it will be essential to pit different refutable causal hypotheses against each other (Lahey, D'Onofrio, & Waldman, 2009; Rutter, 2003, 2006b).
Monographs of the Society for Research in Child Development 04/2010; 75(1):187-211. · 5.50 Impact Factor
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ABSTRACT: A common polymorphism in the serotonin transporter gene (SLC6A4, 5HTT) has been repeatedly shown to moderate the influence of childhood adversity and stressful life events on the development of psychopathology. Using data from the English and Romanian Adoptee Study, a prospective-longitudinal study of individuals (n = 125) exposed to severe early institutional deprivation (ID), we tested whether the effect of ID on adolescent emotional problems is moderated by 5HTT genotype and stressful life events in adolescence.
Emotional problems were assessed using questionnaire data (age 11), and on the basis of the CAPA diagnostic interview (age 15). Additionally, the number of stressful life events was measured.
There was a significant effect for genotype (p = .003) and a gene x environment interaction (p = .008) that was independent of age at testing. Carriers of the s/l and s/s genotype who experienced severe ID showed the highest emotional problem scores, while l/l homozygotes in the severe ID group showed the lowest overall levels. Furthermore, s/s carriers in the severe ID group who experienced a high number of stressful life events between 11 and 15 years had the largest increases in emotional problem scores, while a low number of stressful life events was associated with the largest decrease (4-way interaction: p = .05).
The effects of severe early ID on emotional problems in adolescence are moderated by 5HTT genotype, and influenced by stressful life events in adolescence.
Journal of Child Psychology and Psychiatry 03/2010; 51(7):755-62. · 4.28 Impact Factor
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Jenny Castle,
Christine Groothues,
Celia Beckett,
Emma Colvert,
Amanda Hawkins,
Jana Kreppner, Robert Kumsta,
Wolff Schlotz,
Edmund Sonuga-Barke,
Suzanne Stevens,
Michael Rutter
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ABSTRACT: Parents of 165 children adopted from Romania and 52 children adopted from within the United Kingdom rated the success of the adoptions when the children were 11 years old. As was the case at two earlier study waves, satisfaction was found to be extremely high. Both positive and negative assessments were generally stable between ages 6 and 11, although for the children who had more problems there was an increase in negative evaluation, albeit within an overall positive picture. Parents' evaluations were somewhat more negative for this group of children; however, parents reported that having the child as part of their family was very rewarding. Negative evaluation was not directly related to age at placement, but appeared to be a reflection of the later-placed children's higher rates of problem behavior. As found at earlier assessment waves, child factors, in particular conduct problems and inattention or overactivity, were key in predicting parental evaluations at age 11, as were four domains closely associated with institutional deprivation, namely cognitive impairment, quasi-autistic patterns, inattention or overactivity, and disinhibited attachment. The findings emphasize the need for early intervention for children in severely deprived conditions, and for access to postadoption services that target the particular problem behaviors the children may exhibit.
American Journal of Orthopsychiatry 10/2009; 79(4):522-31. · 1.29 Impact Factor
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ABSTRACT: The aim of the present study was to examine the association between prenatal psychosocial stress exposure and subsequent prefrontal cortex-dependent working memory performance in human adults. Working memory performance was assessed using an item-recognition task under 10 mg hydrocortisone (cortisol) and placebo conditions in a sample of 32 healthy young women (mean age = 25 +/- 4.34 years) whose mothers experienced a major negative life event during their pregnancy (Prenatal Stress, PS group), and in a comparison group of 27 healthy young women (mean age = 24 +/- 3.4 years). The two groups did not differ in the placebo condition, however, subjects in the PS group showed longer reaction times after hydrocortisone administration compared with subjects in the comparison group (p = .02). These findings provide support for an association between prenatal stress exposure and the potential modulatory effect of cortisol on working memory performance in young adults, which may reflect compromised development of the prefrontal cortex in prenatal life.
Behavioral Neuroscience 09/2009; 123(4):886-93. · 2.62 Impact Factor
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ABSTRACT: Early institutional deprivation is a risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms. However not all individuals are affected. We tested the hypothesis that this heterogeneity is influenced by gene x environment (GxE) interaction and that genetic polymorphisms involved in dopamine neurotransmission moderate the effects of severe early institutional deprivation on symptoms of ADHD (sADHD). Using a prospective-longitudinal design sADHD were measured at ages 6, 11, and 15 years in a sample of individuals who experienced severe institutional deprivation (up to 42 months of age) in Romanian orphanages and a non-institutionalized comparison group. Individuals were genotyped for polymorphisms in the dopamine D4 receptor (DRD4 48-bp VNTR in exon 3) and dopamine transporter gene (DAT1 haplotypes combining a 40-bp VNTR in 3'UTR and a 30-bp VNTR in intron 8). The risk for sADHD associated with early institutional deprivation was moderated by the DAT1 but not the DRD4 genotypes; an effect that was first apparent in early-, and persisted to mid-adolescence. The results (i) provide evidence for developmental continuities in G x E interaction, (ii) explain some of the heterogeneity in ADHD outcomes following institutional deprivation and, (iii) add to our understanding of environmental determinants of sADHD.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2009; 150B(6):753-61. · 3.70 Impact Factor
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ABSTRACT: Stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis and results in the secretion of corticosteroids, which facilitate behavioral adaptation and promote the termination of the stress response. These actions exerted by cortisol are mediated by two brain corticosteroid receptor types: the high affinity mineralocorticoid (MR) and the low affinity glucocorticoid receptor (GR). Dexamethasone is a potent GR agonist with affinity to MR. Administration of dexamethasone in the evening results in a significant suppression of the morning cortisol awakening response (CAR). Here we tested the involvement of MR variants in this effect of dexamethasone in 218 young healthy subjects (125 females, all using oral contraceptives). For this purpose we determined two single nucleotide polymorphisms (SNPs) in the MR gene, the previously described MRI180V (rs5522) and the MR-2G/C (rs2070951), which both affect in vitro the transactivational capacity of the MR in response to either cortisol or dexamethasone. Administration of a low dose dexamethasone (0.25mg) at 2300h resulted in a significant suppression of the cortisol awakening response (CAR). Both SNPs modulated the suppression of the CAR after dexamethasone significantly and in a sex specific manner. Suppression of the CAR was highest in the female MR-2G/C GG subjects while in male GG subjects the dexamethasone suppression of the CAR was attenuated compared to the MR-2G/C GC and CC groups. For the MRI180V, male AA subjects showed after dexamethasone a higher CAR than AG subjects while this effect was not observed in females. The SNPs had no significant influence on the CAR without prior dexamethasone treatment. The association of the CAR with functional MR gene variants only in dexamethasone treated subjects suggests the involvement of MR in dexamethasone induced suppression of morning cortisol.
Psychoneuroendocrinology 09/2009; 35(3):339-49. · 5.81 Impact Factor
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ABSTRACT: A key regulator of serotonergic neurotransmission is the serotonin transporter (5-HTT) and a common 5HTT gene promoter polymorphism, termed 5HTTLPR, is associated with phenotypes related to anxiety and depression. Furthermore, the serotonergic system influences hypothalamus-pituitary-adrenal (HPA) axis activity, which, in turn, is related to psychiatric diseases.
To explore the association between the 5-HTTLPR and HPA axis regulation we performed a detailed endophenotyping in 216 healthy subjects (all 126 females used oral contraceptives).
While ACTH and cortisol responses to an established psychosocial stress paradigm (Trier Social Stress Test) were not found to be related to the 5-HTTLPR, we observed a significant and sex-specific association with the cortisol awakening response, which is a reliable marker of basal cortisol secretion, and with ACTH levels after dexamethasone administration. The supplementary inclusion of a 5-HTT A/G polymorphism (rs25531) in the analyses did not substantially modify our results.
These findings support the view that the 5-HTTLPR is associated with a major neuroendocrine stress system. It could be speculated that the sex-specific nature of this association contributes to the distinct gender differences in the vulnerability for depression.
Psychoneuroendocrinology 03/2009; 34(7):972-82. · 5.81 Impact Factor
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ABSTRACT: Epidemiological studies have reported associations between measures of size and weight at birth and disease risk in later life. Alteration in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis in response to prenatal stress has been proposed as one underlying mechanism. The present study investigated in humans the association of prenatal psychosocial stress exposure with subsequent HPA axis regulation in adult life, with a focus on measures of response to challenge and feedback sensitivity. Healthy young adults whose mothers experienced severe stress during their pregnancy in form of major negative life events (e.g. death of someone close; prenatal stress (PS) group, n=31) and an age-matched comparison group (CG, n=30) underwent the Trier Social Stress Test (TSST) and a 1 microg ACTH(1-24) stimulation test. In addition, a diurnal cortisol profile was assessed. ACTH concentrations following a standardized behavioural challenge paradigm (TSST) were marginally significantly higher in PS subjects than in CG subjects (p=.06). Pre-TSST adrenocortical (cortisol) levels were lower (p=.007), whereas the increase in cortisol in response to the TSST was higher (p=.03) in PS subjects compared to CG subjects. Cortisol concentrations following a pharmacological stimulation test simulating pituitary activity (ACTH(1-24) test) were significantly lower in PS than in CG subjects (p=.006). No differences emerged between the two groups in basal diurnal cortisol levels. This study provides first evidence in humans of an association between prenatal psychosocial stress exposure and subsequent alterations in the regulation of the HPA axis.
Hormones and Behavior 12/2008; 55(2):292-8. · 3.87 Impact Factor
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ABSTRACT: To test if the covariance of hypothalamus-pituitary-adrenal (HPA) axis and subjective-psychological responses to stress is dependent on different dynamics of these systems. Although stress theories typically assume substantial correlations of psychological and endocrine stress responses, studies have produced inconsistent results. One reason for this might be imperfect coupling of the different stress response systems. However, inconsistent correlations might also be a result of different on-/offsets of these stress responses, i.e., specific dynamics of the systems.
HPA axis indicators and subjective-psychological states were repeatedly and synchronously measured in a pharmacological challenge test (injection of corticotropin-releasing hormone and infusion of arginine vasopressin; Study 1; n = 42) and a psychosocial stress situation (Trier Social Stress Test; Study 2; n = 219). Cross-correlation analysis was used to test for lag effects in HPA axis reactivity and psychoendocrine responses.
Analyses revealed high cross-correlations of adrenocorticotropic hormone with cortisol responses (up to r = .80 in Study 1 and r = .56 in Study 2) and positive associations of psychological with endocrine stress responses (up to r = .48 in Study 1 and r = .54 in Study 2) at nonzero lags. Subjective-psychological responses preceded HPA axis responses. Moreover, high levels of cortisol were associated with lower later levels of anxiety and activation.
The findings suggest that psychoendocrine stress responses are more closely coupled than previous studies suggested. Due to different dynamics of the systems, endocrine responses lag behind psychological responses.
Psychosomatic Medicine 10/2008; 70(7):787-96. · 3.97 Impact Factor
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ABSTRACT: The aim of the present study was to determine the association between prenatal stress and immune function in human adults. Peripheral blood mononuclear cells (PBMCs) from 34 healthy young women whose mothers experienced major negative life events during their pregnancy (Prenatal Stress, PS group, mean age 25, SD +/- 4.34 years), and from a female comparison group (n = 28, CG, mean age 24 +/- 3.40 years), were stimulated with phytohemagglutinin (PHA), and subsequent cytokine production was measured. A bias for T-helper 2 (Th2) cytokine production due to an overproduction of IL-4 relative to IFN-gamma after PHA stimulation was observed in PS subjects. In addition, IL-6 and IL-10 were also significantly elevated. To the best of our knowledge, this study is the first to suggest a direct association between prenatal stress exposure and alterations in immune parameters in adult women.
Developmental Psychobiology 09/2008; 50(6):579-87. · 2.98 Impact Factor
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ABSTRACT: Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis has been associated with the etiology of major depression. One of the factors underlying altered glucocorticoid signaling might be variability of the glucocorticoid receptor gene (GR, NR3C1). GR polymorphisms have been associated with variability in glucocorticoid sensitivity and endocrine responses to psychosocial stress. Furthermore, a common GR SNP (rs10482605), located in the promoter region, has been associated with major depression. We performed functional characterization of this SNP in vitro using a reporter gene assay under different stimulation conditions. Furthermore, we genotyped 219 subjects previously genotyped for four common GR SNPs to further characterize GR haplotype structure. The minor C allele of the rs10482605 SNP showed reduced transcriptional activity under unstimulated conditions and under different stimulation conditions in two brain derived cell lines. Linkage analyses revealed that the rs10482605 SNP is in high linkage disequilibrium with a A/G SNP in exon 9beta (rs6198), associated with relative glucocorticoid resistance and increased GRbeta mRNA stability. We provide evidence that two functional GR SNPs in linkage disequilibrium are responsible for both regulation of GR expression and mRNA stability. This newly characterized haplotype could increase the risk for the development of stress related disorders, including major depression.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2008; 150B(4):476-82. · 3.70 Impact Factor
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Marcella Rietschel,
Lars Beckmann,
Jana Strohmaier,
Alexander Georgi,
Anna Karpushova,
Frederike Schirmbeck,
Katja V Boesshenz,
Christine Schmäl,
Christin Bürger,
Rami Abou Jamra, [......],
Sonja Entringer,
Axel Krug,
Valentin Markov,
Wolfgang Maier,
Peter Propping,
Stefan Wüst,
Tilo Kircher,
Markus M Nöthen,
Sven Cichon,
Thomas G Schulze
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ABSTRACT: G72 is among the most frequently replicated vulnerability genes for schizophrenia and bipolar disorder. The authors previously found identical haplotypes of markers M23 and M24 to be associated with schizophrenia, bipolar disorder, and panic disorder. Given both the well-recognized familial clustering across these disorders and recent linkage findings implicating the region harboring G72 in the etiology of major depression and panic disorder, we can hypothesize that G72 should also be involved in the etiology of major depression. Neuroticism, measuring trait anxiety, may be the endophenotypic link underlying genetic associations with G72 across diagnostic boundaries. The authors tested whether the previously observed risk haplotypes are also associated with major depression and neuroticism.
The authors performed a standard haplotype analysis in a group of 500 major depression patients and 1,030 population-based comparison subjects. The authors also performed an exploratory analysis on 10 additional G72 markers using a novel haplotype-sharing approach. They performed a quantitative trait haplotype analysis in an independent group of 907 individuals phenotyped for neuroticism.
The previously identified M23-M24 risk haplotype was significantly associated with major depression and high levels of neuroticism. The haplotype-sharing analysis also implicated the same region, whereas more proximal markers showed no association with major depression.
This is the first study to the authors' knowledge to implicate the G72 locus in the etiology of major depression and neuroticism. The results strengthen the notion of a genetic overlap between diagnoses, commonly conceptualized as distinct entities. Neuroticism may constitute the common underlying endophenotypic link.
American Journal of Psychiatry 07/2008; 165(6):753-62. · 12.54 Impact Factor
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ABSTRACT: The human potassium-chloride co-transporter 3 (KCC3, SLC12A6) is involved in cell proliferation and in electro-neutral movement of ions across the cell membrane. The gene (SLC12A6) is located on chromosome 15q14, a region that has previously shown linkage with bipolar disorder, schizophrenia, rolandic epilepsy, idiopathic generalized epilepsy, autism and attention deficit/hyperactivity disorder. Furthermore, recessively inherited mutations of SLC12A6 cause Andermann syndrome, characterized by agenesis of the corpus callosum, which is associated with peripheral neuropathy and psychoses. Recently, we have demonstrated the association of two G/A promoter polymorphisms of SLC12A6 with bipolar disorder in a case-control study, and familial segregation of the rare variants as well as a trend toward association with schizophrenia. To investigate functional consequences of these polymorphisms, lymphocyte DNA was extracted, bisulfite modified, and subsequently sequenced. To investigate SLC12A6 promoter activity, various promoter constructs were generated and analyzed by luciferase reporter gene assays. We provide evidence that the G- allele showed a significant reduction of reporter gene expression. In human lymphocytes, the allele harboring the rare upstream G nucleotide was found to be methylated at the adjacent C position, possibly accountable for tissue-specific reduction in gene expression in vivo. Here we demonstrate functionality of an SNP associated with psychiatric disease and our results may represent a functional link between genetic variation and an epigenetic modification.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2008; 34(2):458-67. · 6.99 Impact Factor
