Shared polygenic risk for ADHD, executive dysfunction and other psychiatric disorders
Shared polygenic risk for ADHD, executive dysfunction and other psychiatric disorders
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ADHD、执行功能障碍和其他精神疾病的共同多基因风险
DOI：
10.1038/s41398-020-00872-9
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发表时间：
2020-06-09
影响因子：
6.8
通讯作者：
Faraone, Stephen, V
中科院分区：
文献类型：
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作者：
Chang, Suhua;Yang, Li;Faraone, Stephen, V
许多精神疾病与执行功能受损（EF）有关。相关的EF组分因精神疾病而异，这种变化可能是由于遗传易感性。我们采用多基因风险评分（PRS）方法探讨了临床招募的注意缺陷多动障碍（ADHD）儿童中5种精神疾病与EF之间的遗传关联。使用全基因组关联研究（GWAS）的ADHD、重性抑郁症（MDD）、精神分裂症（SZ）、双相情感障碍（BIP）和自闭症的汇总数据计算PRS。在中国ADHD队列（n = 1147）中，通过Stroop测试（抑制控制）、线索制作测试（认知灵活性）和数字广度测试（工作记忆）评估EF。探索性因素分析的三个措施确定了一个主成分EF（EF-PC）。使用线性回归模型分析每个PRS和EF测量之间的关联。还分析了EF措施在介导PRS对ADHD症状的影响中的作用。结果表明，抑郁障碍、注意缺陷多动障碍和BIP的PRS与EF-PC均显著相关。对于每一个EF成分，五种精神疾病的PRS的关联结果是不同的：ADHD和MDD的PRS与抑制控制相关（校正后的P = 0.0183和0.0313，分别），BIP的PRS与工作记忆相关（校正后的P = 0.0416），SZ的PRS与认知灵活性相关（校正后的P = 0.0335）。所有这三项EF指标均与ADHD症状显著相关。在中介效应分析中，与抑制控制相关的ADHD和MDD PRS通过抑制控制的中介作用对ADHD症状产生显著的间接影响。这些研究结果表明，多基因风险的几种精神疾病影响特定的执行功能障碍的儿童多动症。这些结果有助于阐明每种精神障碍的风险基因与中间认知域之间的关系，这可能有助于进一步阐明风险基因，并激励努力开发EF测量作为诊断标志物和未来的治疗目标。
Many psychiatric disorders are associated with impaired executive functioning (EF). The associated EF component varies by psychiatric disorders, and this variation might be due to genetic liability. We explored the genetic association between five psychiatric disorders and EF in clinically-recruited attention deficit hyperactivity disorder (ADHD) children using polygenic risk score (PRS) methodology. Genome-wide association study (GWAS) summary data for ADHD, major depressive disorder (MDD), schizophrenia (SZ), bipolar disorder (BIP) and autism were used to calculate the PRSs. EF was evaluated by the Stroop test for inhibitory control, the trail-making test for cognitive flexibility, and the digital span test for working memory in a Chinese ADHD cohort (n=1147). Exploratory factor analysis of the three measures identified one principal component for EF (EF-PC). Linear regression models were used to analyze the association between each PRS and the EF measures. The role of EF measures in mediating the effects of the PRSs on ADHD symptoms was also analyzed. The result showed the PRSs for MDD, ADHD and BIP were all significantly associated with the EF-PC. For each EF component, the association results were different for the PRSs of the five psychiatric disorders: the PRSs for ADHD and MDD were associated with inhibitory control (adjusted P=0.0183 and 0.0313, respectively), the PRS for BIP was associated with working memory (adjusted P=0.0416), and the PRS for SZ was associated with cognitive flexibility (adjusted P=0.0335). All three EF measures were significantly correlated with ADHD symptoms. In mediation analyses, the ADHD and MDD PRSs, which were associated with inhibitory control, had significant indirect effects on ADHD symptoms through the mediation of inhibitory control. These findings indicate that the polygenic risks for several psychiatric disorders influence specific executive dysfunction in children with ADHD. The results helped to clarify the relationship between risk genes of each mental disorder and the intermediate cognitive domain, which may further help elucidate the risk genes and motivate efforts to develop EF measures as a diagnostic marker and future treatment target.