TY - JOUR
T1 - A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder
AU - 23 and Me Research Team
AU - Psychiatric Genomics Consortium: ADHD Subgroup
AU - iPSYCH–Broad ADHD Workgroup
AU - Martin, Joanna
AU - Walters, Raymond K.
AU - Demontis, Ditte
AU - Mattheisen, Manuel
AU - Lee, S. Hong
AU - Robinson, Elise
AU - Brikell, Isabell
AU - Ghirardi, Laura
AU - Larsson, Henrik
AU - Lichtenstein, Paul
AU - Eriksson, Nicholas
AU - Agee, Michelle
AU - Alipanahi, Babak
AU - Auton, Adam
AU - Bell, Robert K.
AU - Bryc, Katarzyna
AU - Elson, Sarah L.
AU - Fontanillas, Pierre
AU - Furlotte, Nicholas A.
AU - Hinds, David A.
AU - Hromatka, Bethann S.
AU - Huber, Karen E.
AU - Kleinman, Aaron
AU - Litterman, Nadia K.
AU - McIntyre, Matthew H.
AU - Mountain, Joanna L.
AU - Northover, Carrie A.M.
AU - Pitts, Steven J.
AU - Sathirapongsasuti, J. Fah
AU - Sazonova, Olga V.
AU - Shelton, Janie F.
AU - Shringarpure, Suyash
AU - Tian, Chao
AU - Tung, Joyce Y.
AU - Vacic, Vladimir
AU - Wilson, Catherine H.
AU - Albayrak, Özgür
AU - Anney, Richard J.L.
AU - Vasquez, Alejandro Arias
AU - Arranz, Maria Jesús
AU - Asherson, Philip
AU - Banaschewski, Tobias J.
AU - Bau, Claiton
AU - Biederman, Joseph
AU - Mortensen, Preben Bo
AU - Freitag, Christine
AU - Kuntsi, Jonna
AU - Neale, Benjamin M.
AU - Sonuga-Barke, Edmund J.S.
AU - Yang, Li
N1 - Funding Information:
This work was supported by the National Human Genome Research Institute of the National Institutes of Health (NIH) (Grant No. R44HG006981 to the 23andMe Team), the Wellcome Trust (Grant No. 106047 to JM). the Australian National Health and Medical Research Council (Grant Nos. 1078901 and 1087889 to NRW). The Broad Institute and Massachusetts General Hospital investigators acknowledge support from the Stanley Medical Research Institute and NIH grants: Grant No. 1R01MH094469 (principal investigator, BMN) and Grant No. 1R01MH107649-01 (principal investigtor, BMN). The iPSYCH team acknowledges funding from the Lundbeck Foundation (Grant Nos. R102-A9118 and R155-2014-1724 ), the Stanley Medical Research Institute, the European Research Council (Project No. 294838), the European Community’s Horizon 2020 Programme (H2020/2014-2020) under Grant No. 667302 (Comorbid Conditions of ADHD), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and grants from Aarhus and Copenhagen universities and university hospitals , including support to the Centre for Integrative Sequencing, the GenomeDK HPC facility, and the Centre for Integrated Register-Based Research at Aarhus University.
Funding Information:
This work was supported by the National Human Genome Research Institute of the National Institutes of Health (NIH) (Grant No. R44HG006981 to the 23andMe Team), the Wellcome Trust (Grant No. 106047 to JM). the Australian National Health and Medical Research Council (Grant Nos. 1078901 and 1087889 to NRW). The Broad Institute and Massachusetts General Hospital investigators acknowledge support from the Stanley Medical Research Institute and NIH grants: Grant No. 1R01MH094469 (principal investigator, BMN) and Grant No. 1R01MH107649-01 (principal investigtor, BMN). The iPSYCH team acknowledges funding from the Lundbeck Foundation (Grant Nos. R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, the European Research Council (Project No. 294838), the European Community's Horizon 2020 Programme (H2020/2014-2020) under Grant No. 667302 (Comorbid Conditions of ADHD), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and grants from Aarhus and Copenhagen universities and university hospitals, including support to the Centre for Integrative Sequencing, the GenomeDK HPC facility, and the Centre for Integrated Register-Based Research at Aarhus University.
Publisher Copyright:
© 2017 Society of Biological Psychiatry
PY - 2018/6/15
Y1 - 2018/6/15
N2 - 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 rg 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.
AB - 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 rg 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.
KW - ADHD
KW - Epidemiology
KW - GWAS
KW - Neurodevelopmental disorders
KW - Polygenic risk score analysis
KW - Sex bias
UR - http://www.scopus.com/inward/record.url?scp=85040102598&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2017.11.026
DO - 10.1016/j.biopsych.2017.11.026
M3 - Article
C2 - 29325848
AN - SCOPUS:85040102598
SN - 0006-3223
VL - 83
SP - 1044
EP - 1053
JO - Biological psychiatry
JF - Biological psychiatry
IS - 12
ER -