Garcia-Argibay Miguel, Brikell Isabell, Thapar Anita, Lichtenstein Paul, Lundström Sebastian, Demontis Ditte, Larsson Henrik
School of Medical Sciences, Örebro University, Faculty of Medicine and Health, Örebro, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Biol Psychiatry. 2024 Mar 1;95(5):444-452. doi: 10.1016/j.biopsych.2023.07.017. Epub 2023 Aug 9.
Attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are two highly prevalent disorders that frequently co-occur. Prior evidence from genetic and cohort studies supports an association between ADHD and MDD. However, the direction and mechanisms underlying their association remain unclear. As onset of ADHD occurs in early life, it has been hypothesized that ADHD may cause MDD.
We examined the association of ADHD with MDD using 3 different genetically informed methods to disentangle causality from confounding: 1) a nationwide longitudinal register-based full sibling comparison (N = 1,018,489) adjusting for shared familial confounding; 2) a prospective co-twin control study comprising 16,477 twins (5084 monozygotic and 11,393 dizygotic); and 3) a two-sample Mendelian randomization analysis using the largest available ADHD (N = 225,534) and MDD (N = 500,199) genome-wide association study summary statistics, adjusting for correlated and uncorrelated horizontal pleiotropy.
Sibling and twin comparisons indicated that individuals with ADHD have an increased risk for subsequent development of MDD (hazard ratio = 4.12 [95% CI 3.62-4.69]) after adjusting for shared genetic and familial factors and that ADHD scores endorsed by parents are positively associated with subsequent MDD scores at ages 15 and 18 years (b = 0.07 [95% CI 0.05-0.08] and b = 0.09 [95% CI 0.08-0.11], respectively). Mendelian randomization analyses showed that genetic liability for ADHD is causally related to MDD (odds ratio = 1.15 [95% CI 1.08-1.23]).
Our study provides consistent results across 3 different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.
注意力缺陷多动障碍（ADHD）和重度抑郁症（MDD）是两种高度常见且经常同时出现的疾病。遗传和队列研究的先前证据支持ADHD与MDD之间存在关联。然而，它们关联的方向和机制仍不清楚。由于ADHD在生命早期发病，因此有人推测ADHD可能导致MDD。
我们使用3种不同的遗传信息方法来区分因果关系与混杂因素，研究ADHD与MDD的关联：1）一项基于全国纵向登记的全同胞比较（N = 1,018,489），调整共享的家族混杂因素；2）一项前瞻性双胞胎对照研究，包括16,477对双胞胎（5084对同卵双胞胎和11,393对异卵双胞胎）；3）一项两样本孟德尔随机化分析，使用现有的最大规模ADHD（N = 225,534）和MDD（N = 500,199）全基因组关联研究汇总统计数据，调整相关和不相关的水平多效性。
同胞和双胞胎比较表明，在调整共享的遗传和家族因素后，患有ADHD的个体随后患MDD的风险增加（风险比 = 4.12 [95% CI 3.62 - 4.69]），并且父母认可的ADHD评分与15岁和18岁时随后的MDD评分呈正相关（分别为b = 0.07 [95% CI 0.05 - 0.08]和b = 0.09 [95% CI 0.08 - 0.11]）。孟德尔随机化分析表明，ADHD的遗传易感性与MDD存在因果关系（优势比 = 1.15 [95% CI 1.08 - 1.23]）。
我们的研究在3种不同的遗传信息方法中提供了一致的结果，强化了ADHD与MDD存在因果关系的假设。
