A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder

Joanna Martin; Raymond K. Walters; Ditte Demontis; Manuel Mattheisen; S. Hong Lee; Elise Robinson; Isabell Brikell; Laura Ghirardi; Henrik Larsson; Paul Lichtenstein; Nicholas Eriksson; 23andMe Research Team; Psychiatric Genomics Consortium: ADHD Subgroup; iPSYCH–Broad ADHD Workgroup; Thomas Werge; Merete Nordentoft

doi:10.1016/j.biopsych.2017.11.026

A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder

Joanna Martin, Raymond K. Walters, Ditte Demontis, Manuel Mattheisen, S. Hong Lee, Elise Robinson, Isabell Brikell, Laura Ghirardi, Henrik Larsson, Paul Lichtenstein, Nicholas Eriksson, 23andMe Research Team, Psychiatric Genomics Consortium: ADHD Subgroup, iPSYCH–Broad ADHD Workgroup, Thomas Werge, Merete Nordentoft

Department of Clinical Medicine

68 Citations (Scopus)

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Abstract

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.

Original language	English
Journal	Biological Psychiatry
Volume	83
Issue number	12
Pages (from-to)	1044-1053
Number of pages	10
ISSN	0006-3223
DOIs	https://doi.org/10.1016/j.biopsych.2017.11.026
Publication status	Published - 15 Jun 2018

Keywords

ADHD
Epidemiology
GWAS
Neurodevelopmental disorders
Polygenic risk score analysis
Sex bias

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Martin, J., Walters, R. K., Demontis, D., Mattheisen, M., Lee, S. H., Robinson, E., Brikell, I., Ghirardi, L., Larsson, H., Lichtenstein, P., Eriksson, N., 23andMe Research Team, Psychiatric Genomics Consortium: ADHD Subgroup, iPSYCH–Broad ADHD Workgroup, Werge, T., & Nordentoft, M. (2018). A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder. Biological Psychiatry, 83(12), 1044-1053. https://doi.org/10.1016/j.biopsych.2017.11.026

Martin, J, Walters, RK, Demontis, D, Mattheisen, M, Lee, SH, Robinson, E, Brikell, I, Ghirardi, L, Larsson, H, Lichtenstein, P, Eriksson, N, 23andMe Research Team, Psychiatric Genomics Consortium: ADHD Subgroup, iPSYCH–Broad ADHD Workgroup, Werge, T & Nordentoft, M 2018, 'A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder', Biological Psychiatry, vol. 83, no. 12, pp. 1044-1053. https://doi.org/10.1016/j.biopsych.2017.11.026

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abstract = "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.",

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AU - Martin, Joanna

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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 - 23andMe Research Team

AU - Psychiatric Genomics Consortium: ADHD Subgroup

AU - iPSYCH–Broad ADHD Workgroup

AU - Werge, Thomas

AU - Nordentoft, Merete

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

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JO - Biological Psychiatry

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A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder

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