Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
Biol Psychiatry. 2018 Jun 15;83(12):1044-1053. doi: 10.1016/j.biopsych.2017.11.026. Epub 2017 Dec 2.
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.
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).
Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with r 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).
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.
注意缺陷多动障碍（ADHD）具有显著的遗传性，男性个体中 ADHD 的发病率比女性个体高 2 至 7 倍。我们研究了导致这种性别偏差的两种潜在遗传机制：性别特异性异质性和女性病例中风险负担更高。
我们分析了来自精神疾病基因组学联盟和 iPSYCH 项目（n=20183 例病例，n=35191 例对照）的全基因组常染色体常见变异以及瑞典人口登记数据（n=77905 例病例，n=1874637 例人群对照）。
两种方法的遗传相关分析表明，常见变异效应在两性之间几乎完全共享，r 估计值接近 1。然而，人群数据的分析表明，患有 ADHD 的女性个体可能面临某些共患发育障碍（即自闭症谱系障碍和先天性畸形）的极高风险，这可能表明存在一些临床和病因学异质性。多基因风险评分分析不支持女性病例中 ADHD 常见风险变异的负担更高（比值比[置信区间]1.02[0.98-1.06]，p=0.28）。相反，流行病学的同胞分析显示，患有 ADHD 的女性个体的同胞比患有 ADHD 的男性个体的同胞具有更高的 ADHD 家族风险（比值比[置信区间]1.14[1.11-1.18]，p=1.5E-15）。
总体而言，这项研究基于流行病学分析，支持 ADHD 女性个体具有更高的家族风险负担和一些临床和病因学异质性，但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 患病率的性别偏差。
