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

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.

Keywords: ADHD; Epidemiology; GWAS; Neurodevelopmental disorders; Polygenic risk score analysis; Sex bias.

Figure 1

Genetic correlation estimates for attention-deficit/hyperactivity disorder in male and female individuals obtained from genomic relatedness matrix restricted maximum likelihood (GREML) and linkage disequilibrium score regression (LDSC) for the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Psychiatric Genomics Consortium (PGC), and combined PGC + iPSYCH datasets. Because of strict restrictions on raw individual genotype access and transfer, GREML analyses could only be performed separately in the PGC and iPSYCH samples. Bars display standard errors. The horizontal dashed line indicates a genetic correlation of 1. The estimator was left unconstrained for these analyses to allow for an unbiased assessment of the standard errors of the estimates; as such, some of the estimates exceed 1.

Figure 2

Sex-specific single nucleotide polymorphism (SNP) heritability estimates for attention-deficit/hyperactivity disorder, varying the assumed population prevalence based on different male:female ratios (ranging from 1:1 to 7:1). Estimates are presented for the total available sample of male individuals as well as for a downsampled set of male cases and controls to match the available sample size in female individuals.

Figure 3

Quantile–quantile and Manhattan plots for sex-specific genome-wide association meta-analyses. (A) Female case-control analysis quantile–quantile plot. (B) Female case-control analysis Manhattan plot. (C) Male case-control analysis quantile–quantile plot. (D) Male case-control analysis Manhattan plot. In (B) and (D), the horizontal red (upper) line indicates genome-wide significance (p < 5E-8) and the horizontal green (lower) line indicates suggestive subthreshold signals (p < 5E-6).

Figure 4

Forest plots of meta-analysis results for logistic regression analyses of attention-deficit/hyperactivity disorder polygenic risk scores with case sex as the outcome (A), case-control status in female individuals (B), and case-control status in male individuals (C). Box sizes reflect sample sizes. Refer to Table 1 for exact sample sizes. CIs, confidence intervals; iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research; PGC, Psychiatric Genomics Consortium.