Association of Candidate Genes with Phenotypic Traits Relevant to Anorexia Nervosa (original) (raw)
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Association study of 182 candidate genes in anorexia nervosa
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2010
We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case-control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome-Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing-based rare variant discovery assays, and pathwaybased analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.
The genetics of anorexia nervosa collaborative study: Methods and sample description
International Journal of Eating Disorders, 2008
Objective: Supported by National Institute of Mental Health (NIMH), this 12-site international collaboration seeks to identify genetic variants that affect risk for anorexia nervosa (AN). Method: Four hundred families will be ascertained with two or more individuals affected with AN. The assessment battery produces a rich set of phenotypes comprising eating disorder diagnoses and psychological and personality features known to be associated with vulnerability to eating disorders. Results: We report attributes of the first 200 families, comprising 200 probands and 232 affected relatives. Conclusion: These results provide context for the genotyping of the first 200 families by the Center for Inherited Disease Research. We will analyze our first 200 families for linkage, complete recruitment of roughly 400 families, and then perform final linkage analyses on the complete cohort. DNA, genotypes, and phenotypes will form a national eating disorder repository maintained by NIMH and available to qualified investigators. V V
The Genetics of Anorexia Nervosa: Current Findings and Future Perspectives
International journal of child and adolescent health, 2009
Anorexia nervosa is a perplexing illness with the highest mortality rate of any psychiatric disease. In this paper, we review the genetic research on anorexia nervosa (AN). Family studies have demonstrated that anorexia nervosa is familial, and twin studies have indicated that additive genetic factors contribute to the familial aggregation. Molecular genetic research, including genomewide linkage and case control association studies, have not been successful in identifying DNA variants that are unequivocally involved in the etiology of AN. We provide a critical appraisal of these studies and discuss methodological issues that may be implicated in conflicting results. Furthermore, we discuss issues relevant to genetic research such as the importance of phenotypic refinement, the use of endophenotypes, and the implications for nosology and genetic analysis. Finally, the future of genetic research for AN is discussed in terms of genomewide association studies (GWAS) and the need for es...
Molecular Psychiatry, 2016
4 GCAN (Genetic Consortium for AN), collaborators are shown in the Acknowledgments 5 WTCCC (Wellcome Trust Case Control Consortium 3), collaborators are shown in the Acknowledgments 7 GIANT (Genetic Investigation of ANthropometric Traits) Consortium, collaborators are shown in the Acknowledgments 10 EGG (Early Growth Genetics) Consortium, collaborators are shown in the Acknowledgments 15 Price Foundation Collaborative Group; collaborators are shown in the Acknowledgments 16
A review and primer of molecular genetic studies of anorexia nervosa
The International journal of eating disorders, 2005
Recent research on anorexia nervosa (AN) has focused on examining the genetic underpinnings of its etiology. The current article reviews molecular genetic studies that have focused on this aspect of AN development. Medline and PsychInfo literature searches, in addition to close inspection of study reference sections, were used to identify studies that examined the genetic diathesis for AN. Findings from association studies indicate some role for the serotonin system in the development of AN. Genomic regions on chromosomes 1 and 10 are also likely to harbor susceptibility genes for AN as well as a range of eating pathologies. Findings corroborate those of neurobiologic studies suggesting that alterations in serotonergic functioning may contribute to the pathogenesis of AN. Nonetheless, future molecular genetic research would benefit from larger and more sustained investigations of candidate genes in homogeneous phenotypes.
Evidence for a Susceptibility Gene for Anorexia Nervosa on Chromosome 1
The American Journal of Human Genetics, 2002
Eating disorders, such as anorexia nervosa (AN), have a significant genetic component. In the current study, a genomewide linkage analysis of 192 families with at least one affected relative pair with AN and related eating disorders, including bulimia nervosa, was performed, resulting in only modest evidence for linkage, with the highest nonparametric linkage (NPL) score, 1.80, at marker D4S2367 on chromosome 4. Since the reduction of sample heterogeneity would increase power to detect linkage, we performed linkage analysis in a subset ( ) of families n p 37 in which at least two affected relatives had diagnoses of restricting AN, a clinically defined subtype of AN characterized by severe limitation of food intake without the presence of binge-eating or purging behavior. When we limited the linkage analysis to this clinically more homogeneous subgroup, the highest multipoint NPL score observed was 3.03, at marker D1S3721 on chromosome 1p. The genotyping of additional markers in this region led to a peak multipoint NPL score of 3.45, thereby providing suggestive evidence for the presence of an AN-susceptibility locus on chromosome 1p.
A genome-wide association study of anorexia nervosa
Molecular Psychiatry, 2014
We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10 −7 ; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation. Anorexia nervosa (AN) is a complex and often chronic eating disorder characterized by inability to maintain a normal healthy body weight and a persistent fear of weight gain, resulting in extreme emaciation and even death in some cases 1. Previous genetic and epidemiological studies have indicated a multifactorial etiology, where both genetic and environmental factors contribute to disease risk 2-7. As sample sizes have increased, genome-wide association studies (GWASs) of AN have begun to identify risk variants 8-10. To further elucidate the genetic architecture of AN, we performed a GWAS using data from our previously published study 8 consisting of 1,033 AN cases by excluding 212 patients with AN who experienced diagnostic crossover during the course of their illness. Specifically, we excluded patients who migrated from or to binge-eating disorder (BED) or bulimia nervosa (BN) as assessed with the Structured Interview for Anorexic and Bulimic Disorders 11). Although a previous study indicated women with BN were rarely to cross over to AN 12 , we observed ~43% of AN/BN crossover cases falls into this category in our cohort, suggestive of a confounding factor. We hypothesized that this reduction in phenotypic heterogeneity, despite the fact that AN and BN may share some genetic risk factors 13 , would enhance gene discovery. Results Our discovery cohort included a total of 692 female AN cases of non-Hispanic European (NHE) descent. Cases were included if they were diagnosed with restricting type and binge eating/purging type of AN as defined by
The American journal of psychiatry, 2017
The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h(2)SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h(2)SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-ba...
Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa
Molecular Psychiatry, 2017
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 variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10−6), and rs7700147, an intergenic variant (P=2.93 × 10−5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, ...