MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; Wolfson Centre for Young People's Mental Health, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
Biol Psychiatry. 2023 Jan 1;93(1):37-44. doi: 10.1016/j.biopsych.2022.06.008. Epub 2022 Jun 14.
Attention-deficit/hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e., direct) and nontransmitted (i.e., indirect) common variant risks. Using parent-offspring trios, we tested whether polygenic liability for neurodevelopmental and psychiatric disorders and lower cognitive ability is overtransmitted to ADHD probands. We also tested for indirect or genetic nurture effects by examining whether nontransmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative of the clinical ADHD population.
Polygenic risk scores (PRSs) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder, schizophrenia, Tourette syndrome, and cognitive ability were calculated in UK control subjects (n = 5081), UK probands with ADHD (n = 857), their biological parents (n = 328 trios), and also a replication sample of 844 ADHD trios.
ADHD PRSs were overtransmitted and cognitive ability and obsessive-compulsive disorder PRSs were undertransmitted. These results were independently replicated. Overtransmission of polygenic liability was not observed for other disorders. Nontransmitted alleles were not enriched for ADHD liability compared with control subjects. Probands from incomplete trios had more hyperactive-impulsive and conduct disorder symptoms, lower IQ, and lower socioeconomic status than complete trios. PRS did not vary by trio status.
The results support direct transmission of polygenic liability for ADHD and cognitive ability from parents to offspring, but not for other neurodevelopmental/psychiatric disorders. They also suggest that nontransmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be nonrandom, in terms of demographic and clinical factors.
注意力缺陷/多动障碍（ADHD）具有高度遗传性，但对于传递（即直接）和非传递（即间接）常见变异风险的相对影响知之甚少。我们使用父母-子女三体型来测试神经发育和精神障碍以及较低认知能力的多基因易感性是否会过度传递给 ADHD 先证者。我们还通过检查非传递的 ADHD 多基因易感性是否升高来测试间接或遗传养育效应。最后，我们检查了完整的三体型是否代表了临床 ADHD 人群。
在英国对照受试者（n=5081）、英国 ADHD 先证者（n=857）、他们的生物父母（n=328 个三体型）以及 844 个 ADHD 三体型的复制样本中，计算了 ADHD、焦虑、自闭症、双相情感障碍、抑郁、强迫症、精神分裂症、妥瑞氏症和认知能力的多基因风险评分（PRS）。
ADHD PRS 过度传递，认知能力和强迫症 PRS 传递不足。这些结果得到了独立的复制。其他疾病未观察到多基因易感性的传递。与对照受试者相比，非传递等位基因并不富集 ADHD 易感性。不完整三体型的先证者比完整三体型的先证者具有更多的多动冲动和品行障碍症状、较低的智商和较低的社会经济地位。PRS 不受三体型状态的影响。
这些结果支持 ADHD 和认知能力的多基因易感性从父母直接传递给子女，但不支持其他神经发育/精神障碍。它们还表明，非传递的神经发育/精神障碍父母等位基因不会通过遗传养育间接导致 ADHD。此外，在人口统计学和临床因素方面，完整 ADHD 三体型的确定可能是非随机的。
