Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.
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ABSTRACT:
SUBMITTER: Huckins LM
PROVIDER: S-EPMC5828108 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
Publications
Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.
Huckins L M LM Hatzikotoulas K K Southam L L Thornton L M LM Steinberg J J Aguilera-McKay F F Treasure J J Schmidt U U Gunasinghe C C Romero A A Curtis C C Rhodes D D Moens J J Kalsi G G Dempster D D Leung R R Keohane A A Burghardt R R Ehrlich S S Hebebrand J J Hinney A A Ludolph A A Walton E E Deloukas P P Hofman A A Palotie A A Palta P P van Rooij F J A FJA Stirrups K K Adan R R Boni C C Cone R R Dedoussis G G van Furth E E Gonidakis F F Gorwood P P Hudson J J Kaprio J J Kas M M Keski-Rahkonen A A Kiezebrink K K Knudsen G-P GP Slof-Op 't Landt M C T MCT Maj M M Monteleone A M AM Monteleone P P Raevuori A H AH Reichborn-Kjennerud T T Tozzi F F Tsitsika A A van Elburg A A Collier D A DA Sullivan P F PF Breen G G Bulik C M CM Zeggini E E
Molecular psychiatry 20170725 5
Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare var ...[more]
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Project description:BackgroundGenetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.MethodsA secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.ResultsTwo loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h 2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN.ConclusionsOur results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
| S-EPMC9616394 | biostudies-literature
Project description:Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14?860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21?080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
| S-EPMC4325090 | biostudies-literature
Project description:Up until now, no study has looked specifically at epigenomic landscapes throughout twin samples, discordant for Anorexia nervosa (AN). Our goal was to find evidence to confirm the hypothesis that epigenetic variations play a key role in the aetiology of AN. In this study, we quantified genome-wide patterns of DNA methylation using the Infinium Human DNA Methylation EPIC BeadChip array (850K) in DNA samples isolated from whole blood collected from a group of 7 monozygotic twin pairs discordant for AN. Results were then validated performing a genome-wide DNA methylation profiling using DNA extracted from whole blood of a group of non-family related AN patients and a group of healthy controls. Our first analysis using the twin sample revealed 9 CpGs associated to a gene. The validation analysis showed two statistically significant CpGs with the rank regression method related to two genes associated to metabolic traits, PPP2R2C and CHST1. When doing beta regression, 6 of them showed statistically significant differences, including 3 CpGs associated to genes JAM3, UBAP2L and SYNJ2.Finally, the overall pattern of results shows genetic links to phenotypes which the literature has constantly related to AN, including metabolic and psychological traits. The genes PPP2R2C and CHST1 have both been linked to the metabolic traits type 2 diabetes through GWAS studies. The genes UBAP2L and SYNJ2 have been related to other psychiatric comorbidity.
2022-01-31 | GSE186766 | GEO
Project description:Up until now, no study has looked specifically at epigenomic landscapes throughout twin samples, discordant for Anorexia nervosa (AN). Our goal was to find evidence to confirm the hypothesis that epigenetic variations play a key role in the aetiology of AN. In this study, we quantified genome-wide patterns of DNA methylation using the Infinium Human DNA Methylation EPIC BeadChip array ("850 K") in DNA samples isolated from whole blood collected from a group of 7 monozygotic twin pairs discordant for AN. Results were then validated performing a genome-wide DNA methylation profiling using DNA extracted from whole blood of a group of non-family-related AN patients and a group of healthy controls. Our first analysis using the twin sample revealed 9 CpGs associated to a gene. The validation analysis showed two statistically significant CpGs with the rank regression method related to two genes associated to metabolic traits, PPP2R2C and CHST1. When doing beta regression, 6 of them showed statistically significant differences, including 3 CpGs associated to genes JAM3, UBAP2L and SYNJ2. Finally, the overall pattern of results shows genetic links to phenotypes which the literature has constantly related to AN, including metabolic and psychological traits. The genes PPP2R2C and CHST1 have both been linked to the metabolic traits type 2 diabetes through GWAS studies. The genes UBAP2L and SYNJ2 have been related to other psychiatric comorbidity.
| S-EPMC8748827 | biostudies-literature
Project description:Anorexia Nervosa (AN) is a disorder characterised by compulsive behaviour, such as self-starvation and excessive exercise, which develop in the pursuit of weight-loss. Recent theory suggests that once established, compulsive weight-loss behaviours in AN may become habitual. In two parallel studies, we measured whether individuals with AN showed a bias toward habits using two outcome-devaluation tasks. In Study 1, 23 women with AN (restrictive and binge/purge subtypes), and 18 healthy controls (HC) completed the slips-of-action paradigm, designed to assess reward-based habits. In Study 2, 13 women with restrictive AN, 14 women recovered from restrictive AN, and 17 female HC participants completed the slips-of-action paradigm, and an avoidance paradigm, designed to assess aversive habits. AN participants showed no deficit relative to HCs in the ability to use feedback to respond correctly to stimuli. Following devaluation of outcomes, all groups in both studies were equally able to withhold inappropriate responses, suggesting no deficit in the balance between goal-directed and habitual control of behaviour in these tasks in AN. These results suggest that individuals with AN do not show a generalised tendency to rely on habits in two outcome-devaluation tasks. Future research is needed to investigate the potential role of disorder-specific habits in the maintenance of behaviour in AN.
| S-EPMC5718042 | biostudies-literature
Project description:ObjectivesRecent neuroimaging studies have indicated that the mesolimbic pathway, known to work as reward neuronal circuitry, regulates cognitive-behavioral flexibility in prolonged anorexia nervosa (AN). Although AN is associated with the highest mortality rate among psychiatric disorders, there have been few neuropathological studies on this topic. This study aims to identify alterations of the reward circuitry regions, especially in the nucleus accumbens (NAcc), using AN brain tissues.MethodsThe neuronal networks in AN cases and controls were examined by immunohistochemistry directed at tyrosine hydroxylase (TH; dopaminergic neuron marker) and glial fibrillary acidic protein (GFAP; astrocyte marker). We also immunochemically analyzed frozen samples presenting astrogliosis, especially in the NAcc and striatum.ResultsHistologically, neuronal deformation with cytoplasmic shrinkage was seen in reward-related brain regions, such as the orbitofrontal cortex/anterior cingulate cortex. The NAcc showed massive GFAP-positive astrocytes and dot-like protrusions of astrocytes in the shell compartment. In the shell, TH and GFAP immunoreactivities revealed prominent astrogliosis within striosomes, which receive projection from the ventral tegmental area (VTA). The numbers of GFAP-positive astrocytes in the NAcc (P = 0.0079) and VTA (P = 0.0025) of AN cases were significantly higher than those of controls. Strongly immunoreactive 18 to 25 kDa bands, which might represent degradation products, were detected only in the NAcc of AN cases. Clinically, all cases presented cognitive rigidity, which might reflect a deficit of the reward pathway.ConclusionOur findings suggest impaired dopaminergic innervation between the NAcc and VTA in AN. Functional dysconnectivity in the reward-related network might induce neuropsychiatric symptoms associated with AN.
| S-EPMC9314851 | biostudies-literature
Project description:Anorexia nervosa (AN) is a heritable eating disorder (50-60%) with an array of commonly comorbid psychiatric disorders and related traits. Although significant genetic correlations between AN and psychiatric disorders and related traits have been reported, their shared genetic architecture is largely understudied. We investigated the shared genetic architecture of AN and schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), mood instability (Mood), neuroticism (NEUR), and intelligence (INT). We applied the conditional false discovery rate (FDR) method to identify novel risk loci for AN, and conjunctional FDR to identify loci shared between AN and related phenotypes, to summarize statistics from relevant genome-wide association studies (GWAS). Individual GWAS samples varied from 72,517 to 420,879 participants. Using conditional FDR we identified 58 novel AN loci. Furthermore, we identified 38 unique loci shared between AN and major psychiatric disorders (SCZ, BIP, and MD) and 45 between AN and psychological traits (Mood, NEUR, and INT). In line with genetic correlations, the majority of shared loci showed concordant effect directions. Functional analyses revealed that the shared loci are involved in 65 unique pathways, several of which overlapped across analyses, including the "signal by MST1" pathway involved in Hippo signaling. In conclusion, we demonstrated genetic overlap between AN and major psychiatric disorders and related traits, and identified novel risk loci for AN by leveraging this overlap. Our results indicate that some shared characteristics between AN and related disorders and traits may have genetic underpinnings.
| S-EPMC10474135 | biostudies-literature
Project description:Background and hypothesisSchizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated.Study designUsing summary statistics from recent large genome-wide association studies on SCZ (Ncases = 53 386) and AN (Ncases = 16 992), a 2-sample Mendelian randomization analysis was conducted to explore the causal relationship between SCZ and AN. MiXeR was employed to quantify their polygenic overlap. A conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was adopted to identify loci jointly associated with both disorders. Functional annotation and enrichment analyses were performed on the shared loci.Study resultsWe observed a cross-trait genetic enrichment, a suggestive bidirectional causal relationship, and a considerable polygenic overlap (Dice coefficient = 62.2%) between SCZ and AN. The proportion of variants with concordant effect directions among all shared variants was 69.9%. Leveraging overlapping genetic associations, we identified 6 novel loci for AN and 33 novel loci for SCZ at condFDR <0.01. At conjFDR <0.05, we identified 10 loci jointly associated with both disorders, implicating multiple genes highly expressed in the cerebellum and pituitary and involved in synapse organization. Particularly, high expression of the shared genes was observed in the hippocampus in adolescence and orbitofrontal cortex during infancy.ConclusionsThis study provides novel insights into the relationship between SCZ and AN by revealing a shared genetic component and offers a window into their complex etiology.
| S-EPMC11349005 | biostudies-literature
Project description:Empathy is the ability to recognize and respond to the emotional states of other individuals. It is an important psychological process that facilitates navigating social interactions and maintaining relationships, which are important for well-being. Several psychological studies have identified difficulties in both self-report and performance-based measures of empathy in a range of psychiatric conditions. To date, no study has systematically investigated the genetic architecture of empathy using genome-wide association studies (GWAS). Here we report the results of the largest GWAS of empathy to date using a well-validated self-report measure of empathy, the Empathy Quotient (EQ), in 46,861 research participants from 23andMe, Inc. We identify 11 suggestive loci (P < 1 × 10-6), though none were significant at P < 2.5 × 10-8 after correcting for multiple testing. The most significant SNP was identified in the non-stratified analysis (rs4882760; P = 4.29 × 10-8), and is an intronic SNP in TMEM132C. The EQ had a modest but significant narrow-sense heritability (0.11 ± 0.014; P = 1.7 × 10-14). As predicted, based on earlier work, we confirmed a significant female advantage on the EQ (P < 2 × 10-16, Cohen's d = 0.65). We identified similar SNP heritability and high genetic correlation between the sexes. Also, as predicted, we identified a significant negative genetic correlation between autism and the EQ (rg = -0.27 ± 0.07, P = 1.63 × 10-4). We also identified a significant positive genetic correlation between the EQ and risk for schizophrenia (rg = 0.19 ± 0.04; P = 1.36 × 10-5), risk for anorexia nervosa (rg = 0.32 ± 0.09; P = 6 × 10-4), and extraversion (rg = 0.45 ± 0.08; 5.7 × 10-8). This is the first GWAS of self-reported empathy. The results suggest that the genetic variations associated with empathy also play a role in psychiatric conditions and psychological traits.
| S-EPMC5845860 | biostudies-literature
Project description:Anorexia nervosa (AN) is a psychiatric disorder with an estimated heritability of around 70%. Although the largest genome-wide association study meta-analysis on AN identified independent loci-conferring risk to the disorder, the molecular mechanisms underlying the genetic basis of AN remains to be elucidated. To explore AN, we ran a transcriptome profiling in peripheral blood mononuclear cells of 15 AN subjects and 15 healthy controls. We validated our mean results in a mouse model of chronic food restriction mimicking several aspects of AN. Through this exploratory study we identified 673 significantly differentially expressed genes in AN. Among these genes, we identified the Vanin-1 (Vnn1) gene that appears to play a major role in the regulation of multiple metabolic pathways. We confirmed an underexpression of Vnn1, especially in the liver, in a mouse model of chronic food restriction. These results indicate that quantitative food restriction affects Vnn1 expression, suggesting that this gene may contribute to the anorexic phenotype in the chronic food restriction mouse model as well as in patients affected by AN. We believe that this report highlights promising candidate genes and gene pathways for AN and reveals Vnn1 as a biomarker that may be used as molecular targets to predict and/or to understand AN.
2023-10-31 | GSE245978 | GEO