Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, United States of America.
Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
PLoS Genet. 2020 Sep 17;16(9):e1009036. doi: 10.1371/journal.pgen.1009036. eCollection 2020 Sep.
The polygenic nature and the contribution of common genetic variation to autism spectrum disorder (ASD) allude to a high degree of pleiotropy between ASD and other psychiatric and behavioral traits. In a pleiotropic system, a single genetic variant contributes small effects to several phenotypes or disorders. While analyzed broadly, there is a paucity of research studies investigating the shared genetic information between specific neurodevelopmental domains and ASD. We performed a phenome-wide association study of ASD polygenetic risk score (PRS) against 491 neurodevelopmental subdomains ascertained in 4,309 probands from the Philadelphia Neurodevelopmental Cohort (PNC) who lack an ASD diagnosis. Our main analysis calculated ASD PRS in 4,309 PNC probands using the per-SNP effects reported in a recent genome-wide association study of ASD in a case-control design. In a high-resolution manner, our main analysis regressed ASD PRS against 491 neurodevelopmental phenotypes with age, sex, and ten principal components of ancestry as covariates. Follow-up analyses included in the regression model PRS derived from brain-related traits genetically correlated with ASD. Our main finding demonstrated that 11-17-year old probands with the highest ASD genetic risk were able to identify angry faces (R2 = 1.06%, p = 1.38 × 10-7, pBonferroni-corrected = 1.9 × 10-3). This ability replicated in older probands (>18 years; R2 = 0.55%, p = 0.036) and persisted after covarying with other psychiatric disorders, brain imaging traits, and educational attainment (R2 = 0.2%, p = 0.019). We also detected several suggestive associations between ASD PRS and emotionality and connectedness with others. These data (i) indicate how genetic liability to ASD may influence neurodevelopment in the general population, (ii) reinforce epidemiological findings of heightened ability of ASD cases to predict certain social psychological events based on increased systemizing skills, and (iii) recapitulate theories of imbalance between empathizing and systemizing in ASD etiology.
多基因特性和常见遗传变异对自闭症谱系障碍（ASD）的贡献暗示 ASD 与其他精神和行为特征之间存在高度的多效性。在多效性系统中，单个遗传变异对几种表型或疾病有微小的影响。虽然广泛分析，但研究调查特定神经发育领域与 ASD 之间共享遗传信息的研究很少。我们对 ASD 多基因风险评分（PRS）进行了全表型关联研究，针对的是 4309 名来自费城神经发育队列（PNC）的先证者的 491 个神经发育子域，这些先证者没有 ASD 诊断。我们的主要分析使用最近在 ASD 病例对照设计的全基因组关联研究中报告的每个 SNP 效应，在 4309 名 PNC 先证者中计算 ASD PRS。以高分辨率方式，我们的主要分析将 ASD PRS 回归到 491 个神经发育表型，这些表型的年龄、性别和十个祖先主成分作为协变量。回归模型中包含的后续分析包括与 ASD 遗传相关的与大脑相关的性状衍生的 PRS。我们的主要发现表明，11-17 岁具有最高 ASD 遗传风险的先证者能够识别愤怒的面孔（R2=1.06%，p=1.38×10-7，pBonferroni 校正=1.9×10-3）。在年龄较大的先证者（>18 岁；R2=0.55%，p=0.036）中复制了这一能力，并且在与其他精神障碍、大脑成像特征和教育程度共事后仍然存在（R2=0.2%，p=0.019）。我们还检测到 ASD PRS 与情感和与他人的联系之间的几个提示性关联。这些数据（i）表明 ASD 的遗传易感性如何影响一般人群的神经发育，（ii）强化了基于增加系统思维技能，ASD 病例预测某些社会心理事件的能力增强的流行病学发现，（iii）再现了 ASD 病因中同理心和系统思维之间失衡的理论。
