Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.

• MeSH
• alkoholismus genetika   MeSH
• celogenomová asociační studie MeSH
• depresivní porucha unipolární genetika   MeSH
• fenotyp MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• poruchy příjmu potravy genetika   MeSH
• poruchy spojené s užíváním psychoaktivních látek genetika   MeSH
• poruchy vyvolané užíváním tabáku genetika   MeSH
• rizikové faktory MeSH
• schizofrenie genetika   MeSH
• vazebná nerovnováha MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

• MeSH
• celogenomová asociační studie * MeSH
• dospělí MeSH
• duševní poruchy komplikace   genetika   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci * MeSH
• genomika metody   MeSH
• index tělesné hmotnosti MeSH
• lidé MeSH
• lokus kvantitativního znaku * MeSH
• mentální anorexie etiologie   genetika   patologie   MeSH
• metabolické nemoci komplikace   genetika   MeSH
• prognóza MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

• MeSH
• bipolární porucha klasifikace   genetika   MeSH
• celogenomová asociační studie MeSH
• depresivní porucha unipolární genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetické lokusy * MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• psychotické poruchy genetika   MeSH
• schizofrenie genetika   MeSH
• studie případů a kontrol MeSH
• systémová biologie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH

Objective To determine whether educational attainment is a causal risk factor in the development of coronary heart disease.Design Mendelian randomisation study, using genetic data as proxies for education to minimise confounding.Setting The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors.Participants The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin.Exposure A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education.Main outcome measure Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D).Results Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3×10(-8)). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile.Conclusions This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the development of coronary heart disease. Potential mechanisms could include smoking, body mass index, and blood lipids. In conjunction with the results from studies with other designs, these findings suggest that increasing education may result in substantial health benefits.

• MeSH
• celogenomová asociační studie * MeSH
• koronární nemoc genetika   prevence a kontrola   MeSH
• lidé MeSH
• mendelovská randomizace * MeSH
• pozorovací studie jako téma MeSH
• rizikové faktory MeSH
• společenská třída MeSH
• stupeň vzdělání * MeSH
• zdraví - znalosti, postoje, praxe MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• audiovizuální média MeSH
• časopisecké články MeSH
• Geografické názvy
• Evropa etnologie   MeSH

IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

• MeSH
• alely MeSH
• celogenomová asociační studie * MeSH
• dospělí MeSH
• fenotyp MeSH
• genetická predispozice k nemoci genetika   MeSH
• kohortové studie MeSH
• lidé MeSH
• pořadí narození * MeSH
• riziko MeSH
• schizofrenie genetika   MeSH
• těhotenství MeSH
• věk matky * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Dánsko MeSH

OBJECTIVE: We aimed to assess the association of oral health (OH), dental care (DC) and mouthwash with upper-aerodigestive tract (UADT) cancer risk, and to examine the extent that enzymes involved in the metabolism of alcohol modify the effect of mouthwash. MATERIALS AND METHODS: The study included 1963 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1993 controls. Subjects were interviewed about their oral health and dental care behaviors (which were converted to scores of OH and DC respectively), as well as smoking, alcohol drinking, diet, occupations, medical conditions and socio-economic status. Blood samples were taken for genetic analyses. Mouthwash use was analyzed in relation to the presence of polymorphisms of alcohol-metabolizing genes known to be associated with UADT. Adjusted odds ratios (ORs) and 95%-confidence intervals [CI] were estimated with multiple logistic regression models adjusting for multiple confounders. RESULTS: Fully adjusted ORs of low versus high scores of DC and OH were 2.36[CI=1.51-3.67] and 2.22[CI=1.45-3.41], respectively, for all UADT sites combined. The OR for frequent use of mouthwash use (3 or more times/day) was 3.23[CI=1.68-6.19]. The OR for the rare variant ADH7 (coding for fast ethanol metabolism) was lower in mouthwash-users (OR=0.53[CI=0.35-0.81]) as compared to never-users (OR=0.97[CI=0.73-1.29]) indicating effect modification (pheterogeneity=0.065) while no relevant differences were observed between users and non-users for the variant alleles of ADH1B, ADH1C or ALDH2. CONCLUSIONS: Poor OH and DC seem to be independent risk factors for UADT because corresponding risk estimates remain substantially elevated after detailed adjustment for multiple confounders. Whether mouthwash use may entail some risk through the alcohol content in most formulations on the market remains to be fully clarified.

• MeSH
• kouření MeSH
• lidé MeSH
• nádory hlavy a krku etiologie   MeSH
• nádory jícnu etiologie   MeSH
• orální hygiena * MeSH
• orální zdraví * MeSH
• pití alkoholu MeSH
• rizikové faktory MeSH
• studie případů a kontrol MeSH
• ústní vody * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

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.

• MeSH
• Asijci genetika   MeSH
• běloši genetika   MeSH
• celogenomová asociační studie MeSH
• jaderné proteiny genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• kalcineurin genetika   MeSH
• kulinové proteiny genetika   MeSH
• lidé MeSH
• mentální anorexie genetika   MeSH
• metaanalýza jako téma MeSH
• studie případů a kontrol MeSH
• transportní proteiny genetika   MeSH
• výměnné faktory guaninnukleotidů genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Japonsko MeSH