Zeynep Yilmaz

A genome-wide association study of anorexia nervosa

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.

Binge eating disorder and the dopamine D2 receptor: Genotypes and sub-phenotypes

OBJECTIVE While the study of binge eating disorder (BED) has burgeoned in the past decade, an understanding of its neurobiological underpinnings is still in the early stages. Previous research suggests that BED may be an overeating syndrome characterized by a hyper-responsiveness to reward, and a strong dopamine signaling in the neuro-circuitry that regulates pleasure and appetitive behaviors. We investigated the D2 receptors genes (DRD2/ANKK1) and their relation to the BED phenotype and four sub-phenotypes of BED that reflect an enhanced response to positive food stimuli. METHODS In a sample of 230 obese adults with and without BED, we genotyped five functional markers of the D2 receptor: rs1800497, rs1799732, rs2283265, rs12364283, and rs6277, and assessed binge eating, emotional eating, hedonic eating, and food craving from dimensionally-scored, self-report questionnaires. RESULTS Compared to weight-matched controls, BED was significantly related to the rs1800497 and rs6277 genotypes that reflect enhanced dopamine neurotransmission. BED participants were also less likely to carry the minor T allele of rs2283265. The same markers related to the sub-phenotypes of BED with rs1800497 showing the strongest effects in the predicted direction. CONCLUSIONS This study supports the view that BED may be a condition that has its causal origins in a hypersensitivity to reward - a predisposition that is likely to foster overeating in our current environment with abundant availability of highly palatable and calorically-dense processed foods.

The brain-derived neurotrophic factor gene in suicidal behaviour: a meta-analysis

Suicide is a prominent public health problem. Its aetiology is complex, and the brain-derived neurotrophic factor (BDNF) has been implicated. We performed the first meta-analysis of the functional BDNF marker Val⁶⁶Met (rs6265, 196G>A) in suicidal behaviour using data from 11 previously published samples plus our present sample (total n=3352 subjects, 1202 with history of suicidal behaviour. The meta-analysis including all 12 studies showed a trend for the Met-carrying genotypes and Met allele conferring risk for suicide (random-effects model p=0.096; ORMet-carrier=1.13, 95% CI 0.98-1.30, and random-effects model p=0.032; ORMet=1.16, 95% CI 1.01-1.32, respectively). Furthermore, we found the Met allele and the Met allele-carrying genotypes to be associated with history of suicide attempt (eight studies; allelic meta-analysis--random-effects model: p=0.013; fixed-effects model: p=0.006; genotypic meta-analysis--random-effects model: p=0.017; fixed-effects model: p=0.008). Taken together, the results from our study suggest that BDNF Val⁶⁶Met is involved in suicidality. Further studies are required to elucidate its role in suicidal behaviour.

Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa

OBJECTIVE The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. METHOD 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 [h2SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. RESULTS Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h2SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. CONCLUSIONS Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

Genetics and Epigenetics of Eating Disorders.

Eating disorders (EDs) are serious psychiatric conditions influenced by biological, psychological, and sociocultural factors. A better understanding of the genetics of these complex traits and the development of more sophisticated molecular biology tools have advanced our understanding of the etiology of EDs. The aim of this review is to critically evaluate the literature on the genetic research conducted on three major EDs: anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). We will first review the diagnostic criteria, clinical features, prevalence, and prognosis of AN, BN, and BED, followed by a review of family, twin, and adoption studies. We then review the history of genetic studies of EDs covering linkage analysis, candidate gene association studies, genome-wide association studies, and the study of rare variants in EDs. Our review also incorporates a translational perspective by covering animal models of ED-related phenotypes. Finally, we review the nascent field of epigenetics of EDs and a look forward to future directions for ED genetic research.

COMT Val158Met variant and functional haplotypes associated with childhood ADHD history in women with bulimia nervosa.

Up to one third of patients with bulimia nervosa (BN) report a history of ADHD symptoms, and both disorders may also be associated with dopaminergic abnormalities. COMT gene, coding for an enzyme responsible for the degradation of dopamine, may play a part in the etiology of ADHD and BN. This study aimed to (1) examine if certain variants of the COMT genetic markers (rs6269, rs4633, rs4818 and rs4680) are more common in BN versus controls; (2) assess transmission of COMT alleles in BN families; and (3) explore the role of COMT genotypes and haplotypes in bulimic women with childhood ADHD history. 72 BN probands and unaffected relatives were genotyped for COMT rs4680 (Val158Met) and three adjacent markers. The remaining 165 probands were matched with nonpsychiatric controls. We also investigated if COMT variants and haplotypes were associated with childhood ADHD history in a subgroup of 86 BN probands who completed the Wender Utah Rating Scale (WURS). Our results showed that cases and controls did not differ in COMT allele and haplotype frequencies. In contrast, specific alleles of all four COMT markers and the medium-activity haplotype were preferentially transmitted to the offspring with BN. COMT Val158 allele was overrepresented and the medium-activity haplotype was underrepresented in BN with childhood ADHD history (p=0.010). These findings suggest a possible role for COMT variants and related haplotypes in BN and its subphenotypes. If replicated, these preliminary findings may have implications for the prevention and treatment of BN that emerges in the context of childhood ADHD.

Genetic epidemiology of eating disorders.

Purpose of review We capture recent findings in the field of genetic epidemiology of eating disorders. As analytic techniques evolve for twin, population, and molecular genetic studies, new findings emerge at an accelerated pace. We present the current status of knowledge regarding the role of genetic and environmental factors that influence risk for eating disorders. Recent findings We focus on novel findings from twin studies, population studies using genetically informative designs, and molecular genetic studies. Over the past 2 years, research in this area has yielded insights into: comorbidity with other psychiatric and medical disorders and with metabolic traits; developmental factors associated with the emergence of eating disorders; and the molecular genetics of anorexia nervosa. Summary Insights from genetic epidemiology provide an important explanatory model for patients with eating disorders, family members, and clinicians. Understanding core biological determinants that explain the severity and persistence of the illnesses, their frequent co-occurrence with other conditions, and their familial patterns raises awareness and increases compassion for individuals living with these disorders. Large-scale genomic studies are currently underway. Ultimately, this domain of research may pave the way to greater understanding of the underlying neurobiology and inform the development of novel and effective interventions.

Possible association of the DRD4 gene with a history of attention-deficit/hyperactivity disorder in women with bulimia nervosa

OBJECTIVE Up to one-third of patients with bulimia nervosa (BN) report a history of attention-deficit/hyperactivity disorder (ADHD) symptoms, and the dopaminergic genes, especially the dopamine receptor D4 (DRD4), have been associated independently with both binge eating and ADHD. METHOD The purpose of this study was to (1) compare the frequency of DRD4 exon III VNTR variants in 157 BN probands and equal number of healthy controls; (2) assess transmission of DRD4 alleles in 68 families of patients with BN; and (3) explore the possible role of DRD4 gene in childhood ADHD history in a subgroup of 81 women with BN. RESULTS Our results showed that the BN probands and controls did not differ in DRD4 allele frequency. We also did not find evidence for preferential transmission of any DRD4 variant to the affected offspring with BN. However, the presence of either the 2-repeat or 7-repeat allele was associated with a history of childhood ADHD in BN (p = .038, odds ratio = 3.2). DISCUSSION Our findings suggest that although DRD4 may not be associated with the diagnosis of BN, its variants are associated with a history of childhood ADHD in BN probands. This may have relevance for the understanding, prevention, and treatment of BN that evolves in the context of childhood ADHD.

Investigation of the genetic interaction between BDNF and DRD3 genes in suicidical behaviour in psychiatric disorders

Abstract Objectives. Suicide is a serious public health concern, and it is partly genetic. The brain-derived neurotrophic factor (BDNF) gene has been a strong candidate in genetic studies of suicide (Dwivedi et al., Arch Gen Psychiatry 2010;60:804–815; Zai et al., Prog Neuropsychopharmacol Biol Psychiatry 2012;34:1412–1418) and BDNF regulates the expression of the dopamine D3 receptor. Objective. We examined the role of the BDNF and DRD3 genes in suicide. Methods. We analysed four tag single-nucleotide polymorphisms (SNPs) in BDNF and 15 SNPs in the D3 receptor gene DRD3 for possible association with suicide attempt history in our Canadian sample of Schizophrenia (SCZ) patients of European ancestry (N = 188). Results. In this sample, we found a possible interaction between the BDNF Val66Met and DRD3 Ser9Gly SNPs in increasing the risk of suicide attempt(s) in our SCZ sample. Specifically, a larger proportion of SCZ patients who were carrying at least one copy of the minor allele at each of the Val66Met and Ser9Gly functional markers have attempted suicides compared to patients with other genotypes (Bonferroni P < 0.05). However, we could not replicate this finding in samples from other psychiatric populations. Conclusions. Taken together, the results from the present study suggest that an interaction between BDNF and DRD3 may not play a major role in the risk for suicide attempt, though further studies, especially in SCZ, are required.

Genetic study of neuregulin 1 and receptor tyrosine-protein kinase erbB-4 in tardive dyskinesia

Abstract Objectives: Tardive dyskinesia (TD) is a movement disorder that may develop as a side effect of antipsychotic medication. The aetiology underlying TD is unclear, but a number of mechanisms have been proposed. Methods: We investigated single-nucleotide polymorphisms (SNPs) in the genes coding for neuregulin-1 and erbB-4 receptor in our sample of 153 European schizophrenia patients for possible association with TD. Results: We found the ERBB4 rs839523 CC genotype to be associated with risk for TD occurrence and increased severity as measured by the Abnormal Involuntary Movement Scale (AIMS) (P = .003). Conclusions: This study supports a role for the neuregulin signalling pathway in TD, although independent replications are warranted.