Observational studies suggest that child maltreatment increases the risk of externalizing spectrum disorders such as attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), antisocial personality disorder (ASPD), and substance use disorder (SUD). Yet, only few of such associations have been investigated by approaches that provide strong evidence for causation, such as Mendelian Randomization (MR). Establishing causal inference is essential given the growing recognition of gene-environment correlations, which can confound observational research in the context of childhood maltreatment. Evaluating causality between child maltreatment and the externalizing phenotypes, we used genome-wide association study (GWAS) summary data for child maltreatment (143,473 participants), ADHD (20,183 cases; 35,191 controls), CD (451 cases; 256,859 controls), ASPD (381 cases; 252,877 controls), alcohol use disorder (AUD; 13,422 cases; 244,533 controls), opioid use disorder (OUD; 775 cases; 255,921 controls), and cannabinoid use disorder (CUD; 14,080 cases; 343,726 controls). We also generated a latent variable ‘common externalizing factor’ (EXT) using genomic structural equation modeling. Genetically predicted childhood maltreatment was consistently associated with ADHD (odds ratio [OR], 10.09; 95%-CI, 4.76–21.40; P = 1.63 × 10⁻⁰⁹), AUD (OR, 3.72; 95%-CI, 1.85–7.52; P = 2.42 × 10⁻⁰⁴), and the EXT (OR, 2.64; 95%-CI, 1.52–4.60; P = 5.80 × 10⁻⁰⁴) across the different analyses and pleiotropy-robust methods. A subsequent GWAS on childhood maltreatment and the externalizing dimension from Externalizing Consortium (EXT-CON) confirmed these results. Two of the top five genes with the strongest associations in EXT GWAS, CADM2 and SEMA6D, are also ranked among the top 10 in the EXT-CON. The present results confirm the existence of a common externalizing factor and an increasing vulnerability caused by child maltreatment, with crucial implications for prevention. However, the partly diverging results also indicate that specific influences impact individual phenotypes separately.

观察性研究表明，虐待儿童会增加外化谱系障碍的风险，例如注意力缺陷多动障碍（ADHD）、品行障碍（CD）、反社会人格障碍（ASPD）和物质使用障碍（SUD）。然而，只有少数此类关联通过孟德尔随机化 (MR) 等为因果关系提供有力证据的方法进行了研究。鉴于人们日益认识到基因与环境的相关性，建立因果推断至关重要，这可能会混淆儿童虐待背景下的观察性研究。为了评估儿童虐待与外化表型之间的因果关系，我们使用了儿童虐待（143,473 名参与者）、ADHD（20,183 例；35,191 名对照）、CD（451 例；256,859 名对照）、ASPD（451 例；256,859 名对照）的全基因组关联研究（GWAS）汇总数据。 381 例；252,877 例对照）、酒精使用障碍（AUD；13,422 例；244,533 例对照）、阿片类药物使用障碍（OUD；775 例；255,921 例对照）和大麻素使用障碍（CUD；14,080 例；343,726 例对照）。我们还使用基因组结构方程模型生成了一个潜在变量“共同外化因子”（EXT）。基因预测的儿童期虐待与 ADHD 一致相关（比值比 [ OR ], 10.09; 95%-CI, 4.76–21.40; P = 1.63 × 10 ⁻⁰⁹ ），AUD ( OR , 3.72; 95%-CI, 1.85–7.52 ; P = 2.42 × 10 ⁻⁰⁴ )，以及不同分析和多效性稳健方法的 EXT ( OR , 2.64; 95%-CI, 1.52–4.60; P = 5.80 × 10 ⁻⁰⁴ )。随后由外化联盟 (EXT-CON) 进行的关于儿童虐待和外化维度的 GWAS 证实了这些结果。 EXT GWAS 关联性最强的前 5 个基因中，CADM2 和 SEMA6D 中的两个基因也在 EXT-CON 中跻身前 10 名。目前的结果证实，存在一个共同的外在因素，并且虐待儿童造成的脆弱性日益增加，这对预防具有至关重要的影响。然而，部分不同的结果也表明特定的影响分别影响个体表型。