Pirooznia Mehdi, Niranjan Tejasvi, Chen Yun-Ching, Tunc Ilker, Goes Fernando S, Avramopoulos Dimitrios, Potash James B, Huganir Richard L, Zandi Peter P, Wang Tao
Bioinformatics and Computational Biology Core Facility, National Heart Lung and Blood Institute, NIH, Bethesda, MD, United States.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Front Genet. 2019 Nov 27;10:1186. doi: 10.3389/fgene.2019.01186. eCollection 2019.
Autism spectrum disorders (ASDs) are characterized by deficits in three core behavioral domains: reciprocal social interactions, communication, and restricted interests and/or repetitive behaviors. Several hundreds of risk genes for autism have been identified, however, it remains a challenge to associate these genes with specific core behavioral deficits. In multiplex autism families, affected sibs often show significant differences in severity of individual core phenotypes. We hypothesize that a higher mutation burden contributes to a larger difference in the severity of specific core phenotypes between affected sibs. We tested this hypothesis on social behavioral deficits in autism. We sequenced synaptome genes (n = 1,886) in affected male sib-pairs (n = 274) in families from the Autism Genetics Research Exchange (AGRE) and identified rare (MAF ≤ 1%) and predicted functional variants. We selected affected sib-pairs with a large (≥10; n = 92 pairs) or a small (≤4; n = 108 pairs) difference in total cumulative Autism Diagnostic Interview-Revised (ADI-R) social scores (SOCT_CS). We compared burdens of unshared variants present only in sibs with severe social deficits and found a higher burden in SOCT_CS≥10 compared to SOCT_CS ≤ 4 (SOCT_CS≥10: 705.1 ± 16.2; SOCT_CS ≤ 4, 668.3 ± 9.0; = 0.025). Unshared SOCT_CS≥10 genes only in sibs with severe social deficits are significantly enriched in the SFARI gene set. Network analyses of these genes using InWeb_IM, molecular signatures database (MSigDB), and GeNetMeta identified enrichment for phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) (Enrichment Score [eScore] value = 3.36E-07; n = 8 genes) and Nerve growth factor (NGF) (eScore value = 8.94E-07; n = 9 genes) networks. These studies support a key role for these signaling networks in social behavioral deficits and present a novel approach to associate risk genes and signaling networks with core behavioral domains in autism.
自闭症谱系障碍（ASD）的特征在于三个核心行为领域存在缺陷：相互的社交互动、沟通以及受限的兴趣和/或重复行为。目前已鉴定出数百个自闭症风险基因，然而，将这些基因与特定的核心行为缺陷联系起来仍然是一项挑战。在多个自闭症家庭中，受影响的兄弟姐妹在个体核心表型的严重程度上往往存在显著差异。我们假设较高的突变负担会导致受影响的兄弟姐妹之间特定核心表型严重程度的差异更大。我们针对自闭症的社交行为缺陷检验了这一假设。我们对来自自闭症遗传学研究交流协会（AGRE）的家庭中受影响的男性兄弟姐妹对（n = 274）的突触体基因（n = 1,886）进行了测序，并鉴定出罕见（最小等位基因频率≤1%）且预测具有功能的变异。我们选择了自闭症诊断访谈修订版（ADI - R）社交总分差异大（≥10；n = 92对）或差异小（≤4；n = 108对）的受影响兄弟姐妹对。我们比较了仅在社交缺陷严重的兄弟姐妹中存在的非共享变异的负担，发现与ADI - R社交总分≤4相比，ADI - R社交总分≥10的负担更高（ADI - R社交总分≥10：705.1 ± 16.2；ADI - R社交总分≤4，668.3 ± 9.0；p = 0.025）。仅在社交缺陷严重的兄弟姐妹中存在的非共享ADI - R社交总分≥10的基因在SFARI基因集中显著富集。使用InWeb_IM、分子特征数据库（MSigDB）和GeNetMeta对这些基因进行网络分析，发现磷脂酰肌醇3 -激酶（PI3K）-AKT - 雷帕霉素哺乳动物靶蛋白（mTOR）网络（富集得分[eScore] p值 = 3.36E - 07；n = 8个基因）和神经生长因子（NGF）网络（eScore p值 = 8.94E - 07；n = 9个基因）有富集。这些研究支持了这些信号网络在社交行为缺陷中的关键作用，并提出了一种将风险基因和信号网络与自闭症核心行为领域联系起来的新方法。
