Journal
BIOLOGICAL PSYCHIATRY
Volume 83, Issue 12, Pages 1044-1053Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2017.11.026
Keywords
ADHD; Epidemiology; GWAS; Neurodevelopmental disorders; Polygenic risk score analysis; Sex bias
Categories
Funding
- National Human Genome Research Institute of the National Institutes of Health (NIH) [R44HG006981]
- Wellcome Trust [106047]
- Australian National Health and Medical Research Council [1078901, 1087889]
- Stanley Medical Research Institute
- NIH [1R01MH094469, 1R01MH107649-01]
- Lundbeck Foundation [R102-A9118, R155-2014-1724]
- European Research Council [294838]
- European Community's Horizon 2020 Programme (H2020/2014-2020) [667302]
- Novo Nordisk Foundation
- Aarhus university
- Copenhagen university
- Merz
- Shire
- Lundbeck
- Rhodes
- Arbor
- KenPharm
- Ironshore
- Akili Interactive Labs
- CogCubed
- Alcobra
- VAYA
- Sunovion
- Genomind
- NeuroLifeSciences
- Neurovance
- Otsuka
- McNeil
- Janssen
- Novartis
- Pfizer
- Eli Lilly
- Lundbeck Foundation [R248-2017-2003] Funding Source: researchfish
- Medical Research Council [MR/L010305/1] Funding Source: researchfish
- Novo Nordisk Fonden [NNF16OC0022018] Funding Source: researchfish
- Wellcome Trust [106047/Z/14/Z] Funding Source: researchfish
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD086984] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R44HG006981] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH107649, R01MH094469, U01MH109536] Funding Source: NIH RePORTER
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BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. METHODS: We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls). RESULTS: Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with r(g) estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15). CONCLUSIONS: Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.
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