Department of Pediatrics III, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Institute of Sex- and Gender-sensitive Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Eur Child Adolesc Psychiatry. 2024 Oct;33(10):3613-3623. doi: 10.1007/s00787-024-02421-x. Epub 2024 Mar 27.
The higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in males raises the question of whether testosterone is implicated in ADHD risk. However, cross-sectional studies did not identify an association between ADHD and testosterone levels. Mendelian randomization (MR) studies can overcome limitations inherent to association studies, especially of reverse causation and residual confounding. In the current study, sex-combined and sex-specific two-sample MR analyses were conducted to address whether testosterone has a causal influence on ADHD risk. Sex-combined as well as sex-specific target-genetic variants for bioavailable testosterone were derived from a large genome-wide association study (GWAS) on up to 382,988 adult white European UK Biobank study participants. In our sex-specific analyses for ADHD, including data from 14,154 males and 4,945 females with ADHD (17,948 and 16,246 controls respectively), no association between bioavailable testosterone and ADHD risk was found, neither in males (inverse-variance weighted (IVW): beta = 0.09, 95%-CI [-0.10, 0.27]) nor in females (IVW: beta=-0.01, 95%-CI [-0.20, 0.19]). However, in the sex-combined analysis, including 38,691 cases and 186,843 controls, genetically predicted bioavailable testosterone was associated with ADHD risk (IVW: beta = 0.24, 95%-CI [0.09, 0.39]). The inclusion of birth weight and/or SHBG as additional variables in multivariable MR analyses did not alter this result. However, when correcting for potential BMI-driven pleiotropy by a multivariable MR study, all effect estimates for testosterone showed non-significant results. Taken together, no robust evidence for a causal effect of bioavailable testosterone on the risk for ADHD was found.
男性中注意缺陷多动障碍（ADHD）的患病率较高，这就提出了一个问题，即睾丸酮是否与 ADHD 风险有关。然而，横断面研究并未发现 ADHD 与睾丸酮水平之间存在关联。孟德尔随机化（MR）研究可以克服关联研究固有的局限性，特别是反向因果关系和残留混杂的问题。在本研究中，进行了男女混合和性别特异性两样本 MR 分析，以确定睾丸酮是否对 ADHD 风险有因果影响。可利用睾丸酮的男女混合及性别特异性靶向遗传变异来自于一项多达 382988 名成年白种欧洲人 UK Biobank 研究参与者的全基因组关联研究（GWAS）。在我们针对 ADHD 的性别特异性分析中，包括了 14154 名男性和 4945 名女性 ADHD 患者（分别为 17948 名和 16246 名对照）的数据，没有发现可利用睾丸酮与 ADHD 风险之间存在关联，无论在男性中（逆方差加权（IVW）：beta=0.09，95%-CI [-0.10, 0.27]）还是女性中（IVW：beta=-0.01，95%-CI [-0.20, 0.19]）。然而，在包括 38691 例病例和 186843 例对照的男女混合分析中，遗传预测的可利用睾丸酮与 ADHD 风险相关（IVW：beta=0.24，95%-CI [0.09, 0.39]）。在多变量 MR 分析中纳入出生体重和/或 SHBG 作为额外变量并没有改变这一结果。然而，当通过多变量 MR 研究校正潜在的 BMI 驱动的混杂时，睾丸酮的所有效应估计值均显示无统计学意义。综上所述，没有发现可利用睾丸酮对 ADHD 风险有因果影响的可靠证据。
