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1.
Addict Biol ; 26(1): e12880, 2021 01.
Article in English | MEDLINE | ID: mdl-32064741

ABSTRACT

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.


Subject(s)
Feeding and Eating Disorders/genetics , Substance-Related Disorders/genetics , Alcoholism/genetics , Depressive Disorder, Major/genetics , Genome-Wide Association Study , Humans , Linkage Disequilibrium , Phenotype , Polymorphism, Single Nucleotide , Risk Factors , Schizophrenia/genetics , Tobacco Use Disorder/genetics
2.
Cell ; 178(4): 850-866.e26, 2019 08 08.
Article in English | MEDLINE | ID: mdl-31398340

ABSTRACT

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.


Subject(s)
Autism Spectrum Disorder/genetics , Genetic Predisposition to Disease/genetics , Pedigree , Protein Interaction Maps/genetics , Animals , Child , Databases, Genetic , Disease Models, Animal , Female , Gene Deletion , Guanylate Kinases/genetics , Humans , Inheritance Patterns/genetics , Machine Learning , Male , Nuclear Family , Promoter Regions, Genetic/genetics , Receptors, Mineralocorticoid/genetics , Risk Factors , Tumor Suppressor Proteins/genetics , Whole Genome Sequencing , Zebrafish/genetics
3.
Nat Genet ; 51(8): 1207-1214, 2019 08.
Article in English | MEDLINE | ID: mdl-31308545

ABSTRACT

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.


Subject(s)
Anorexia Nervosa/etiology , Genetic Predisposition to Disease , Genome-Wide Association Study , Genomics/methods , Mental Disorders/complications , Metabolic Diseases/complications , Quantitative Trait Loci , Adult , Anorexia Nervosa/genetics , Anorexia Nervosa/pathology , Body Mass Index , Case-Control Studies , Female , Humans , Male , Mental Disorders/genetics , Metabolic Diseases/genetics , Phenotype , Prognosis
4.
Contemp Clin Trials ; 74: 61-69, 2018 11.
Article in English | MEDLINE | ID: mdl-30287268

ABSTRACT

BACKGROUND: Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research. METHODS: ANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H. RESULTS: Blood samples and clinical information were collected from 13,363 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable. CONCLUSIONS: Our multi-pronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection. ANGI is a registered clinical trial: clinicaltrials.govNCT01916538; https://clinicaltrials.gov/ct2/show/NCT01916538?cond=Anorexia+Nervosa&draw=1&rank=3.


Subject(s)
Anorexia Nervosa/diagnosis , Adolescent , Adult , Aged , Anorexia Nervosa/genetics , Australia , Case-Control Studies , Denmark , Feeding and Eating Disorders/diagnosis , Female , Humans , Internet , Middle Aged , New Zealand , Patient Selection , Reproducibility of Results , Surveys and Questionnaires , Sweden , United States , Young Adult
5.
Am J Hum Genet ; 99(3): 540-554, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27569545

ABSTRACT

Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. We analyzed 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families. We observed a higher burden of large, rare CNVs, including inherited events, in individuals with ASD than in their unaffected siblings (odds ratio [OR] = 1.7), but the rate of de novo events was significantly lower than in simplex families. In previously characterized ASD risk loci, we identified 49 CNVs, comprising 24 inherited events, 19 de novo events, and 6 events of unknown inheritance, a significant enrichment in affected versus control individuals (OR = 3.3). In 21 of the 30 families (71%) in whom at least one affected sibling harbored an established ASD major risk CNV, including five families harboring inherited CNVs, the CNV was not shared by all affected siblings, indicating that other risk factors are contributing. We also identified a rare risk locus for ASD and language delay at chromosomal region 2q24 (implicating NR4A2) and another lower-penetrance locus involving inherited deletions and duplications of WWOX. The genetic architecture in multiplex families differs from that in simplex families and is complex, warranting more complete genetic characterization of larger multiplex ASD cohorts.


Subject(s)
Autism Spectrum Disorder/genetics , DNA Copy Number Variations/genetics , Genetic Predisposition to Disease/genetics , Chromosomes, Human, Pair 2/genetics , Cohort Studies , Databases, Genetic , Exons/genetics , Female , Gene Duplication/genetics , Genome-Wide Association Study , Humans , Language Development Disorders/genetics , Male , Odds Ratio , Oligonucleotide Array Sequence Analysis , Oxidoreductases/genetics , Penetrance , Promoter Regions, Genetic/genetics , Risk Factors , Sequence Deletion/genetics , Siblings , Tumor Suppressor Proteins/genetics , Untranslated Regions/genetics , WW Domain-Containing Oxidoreductase
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