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.

中文翻译：

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注意缺陷多动障碍患病率中性别偏见的遗传学调查

背景注意力缺陷/多动障碍 (ADHD) 显示出显着的遗传性，男性个体的发病率是女性个体的 2 到 7 倍。我们研究了这种性别偏见背后的两种推定的遗传机制：性别特异性异质性和女性病例的较高风险负担。方法 我们分析了来自 Psychiatric Genomics Consortium 和 iPSYCH 项目（n = 20,183 例，n = 35,191 对照）和瑞典人口登记数据（n = 77,905 例，n = 1,874,637 人口对照）的全基因组常染色体常见变异。结果 使用两种方法的遗传相关性分析表明，跨性别的常见变异效应几乎完全共享，rg 估计值接近 1。然而，对人口数据的分析，表明患有 ADHD 的女性个体在某些合并症发育状况（即自闭症谱系障碍和先天性畸形）方面的风险可能特别高，这可能表明存在一些临床和病因异质性。多基因风险评分分析不支持女性病例中 ADHD 常见风险变异的更高负担（优势比 [置信区间] = 1.02 [0.98–1.06]，p = .28）。相比之下，流行病学兄弟姐妹分析显示，患有 ADHD 的女性的兄弟姐妹比受影响的男性个体的兄弟姐妹患 ADHD 的家族风险更高（优势比 [置信区间] = 1.14 [1.11-1.18]，p = 1.5E-15 ）。结论 总体而言，本研究支持女性多动症患者的家庭风险负担更大，并且存在一些临床和病因异质性，基于流行病学分析。然而，分子遗传学分析表明，常染色体常见变异在很大程度上不能解释 ADHD 患病率的性别偏见。