Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
International Max Planck Research School for Language Sciences, Nijmegen, The Netherlands.
Nat Commun. 2021 Nov 11;12(1):6534. doi: 10.1038/s41467-021-26755-1.
Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are complex co-occurring neurodevelopmental conditions. Their genetic architectures reveal striking similarities but also differences, including strong, discordant polygenic associations with educational attainment (EA). To study genetic mechanisms that present as ASD-related positive and ADHD-related negative genetic correlations with EA, we carry out multivariable regression analyses using genome-wide summary statistics (N = 10,610-766,345). Our results show that EA-related genetic variation is shared across ASD and ADHD architectures, involving identical marker alleles. However, the polygenic association profile with EA, across shared marker alleles, is discordant for ASD versus ADHD risk, indicating independent effects. At the single-variant level, our results suggest either biological pleiotropy or co-localisation of different risk variants, implicating MIR19A/19B microRNA mechanisms. At the polygenic level, they point to a polygenic form of pleiotropy that contributes to the detectable genome-wide correlation between ASD and ADHD and is consistent with effect cancellation across EA-related regions.
自闭症谱系障碍 (ASD) 和注意缺陷多动障碍 (ADHD) 是复杂的共患神经发育疾病。它们的遗传结构揭示了惊人的相似之处，但也存在差异，包括与教育程度 (EA) 强烈、不一致的多基因关联。为了研究表现为 ASD 相关阳性和 ADHD 相关阴性遗传相关性与 EA 的遗传机制，我们使用全基因组汇总统计数据 (N = 10,610-766,345) 进行多变量回归分析。我们的结果表明，EA 相关的遗传变异在 ASD 和 ADHD 结构中是共享的，涉及相同的标记等位基因。然而，与 EA 相关的多基因关联图谱，跨越共享的标记等位基因，对于 ASD 与 ADHD 风险是不一致的，表明存在独立的影响。在单变体水平上，我们的结果表明存在生物学的多效性或不同风险变体的共定位，暗示 MIR19A/19B microRNA 机制。在多基因水平上，它们指向一种多基因形式的多效性，这种多效性导致了 ASD 和 ADHD 之间可检测到的全基因组相关性，并与 EA 相关区域的效应抵消一致。
