Autism spectrum disorder (ASD) is a behaviorally defined condition that manifests in infancy or early childhood as deficits in communication skills and social interactions. Often, restricted and repetitive behaviors (RRBs) accompany this disorder. ASD is polygenic and genetically complex, so we hypothesized that focusing analyses on intermediate core component phenotypes, such as RRBs, can reduce genetic heterogeneity and improve statistical power. Applying this approach, we mined Caucasian genome-wide association studies (GWAS) data from two of the largest ASD family cohorts, the Autism Genetics Resource Exchange and Autism Genome Project (AGP). Of the 12 RRBs measured by the Autism Diagnostic Interview-Revised, seven were found to be significantly familial and substantially variable, and hence, were tested for genome-wide association in 3104 ASD-affected children from 2045 families. Using a stringent significance threshold (P<7.1 × 10^-9), GWAS in the AGP revealed an association between 'the degree of the repetitive use of objects or interest in parts of objects' and rs2898883 (P<6.8 × 10^-9), which resides within the sixth intron of PHB. To identify the candidate target genes of the associated single-nucleotide polymorphisms at that locus, we applied chromosome conformation studies in developing human brains and implicated three additional genes: SLC35B1, CALCOCO2 and DLX3. Gene expression, brain imaging and fetal brain expression quantitative trait locus studies prioritize SLC35B1 and PHB. These analyses indicate that GWAS of single heritable features of genetically complex disorders followed by chromosome conformation studies in relevant tissues can be successful in revealing novel risk genes for single core features of ASD.

中文翻译：

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自闭症谱系障碍（ASD）限制性和重复性行为与 17q21.33 相关：胎儿大脑中表达优先的基因。

自闭症谱系障碍 (ASD) 是一种行为定义的疾病，在婴儿期或幼儿期表现为沟通技巧和社交互动的缺陷。通常，这种疾病伴随着限制性和重复性行为（RRB）。ASD 是多基因且遗传复杂的，因此我们假设重点分析中间核心成分表型（例如 RRB）可以减少遗传异质性并提高统计功效。应用这种方法，我们从两个最大的 ASD 家族群体——自闭症遗传学资源交换和自闭症基因组计划 (AGP) 中挖掘了白人全基因组关联研究 (GWAS) 数据。在自闭症诊断访谈修订版测量的 12 个 RRB 中，有 7 个被发现具有显着的家族性和显着的变异性，因此，对来自 2045 个家庭的 3104 名受 ASD 影响的儿童进行了全基因组关联性测试。使用严格的显着性阈值 (P<7.1 × 10 ^-9 )，AGP 中的 GWAS 揭示了“重复使用物体或对物体部分感兴趣的程度”与 rs2898883 之间的关联 (P<6.8 × 10 ^-9 ) ，位于 PHB 的第六个内含子内。为了确定该位点相关单核苷酸多态性的候选靶基因，我们在发育中的人脑中应用了染色体构象研究，并涉及了另外三个基因：SLC35B1、CALCOCO2 和 DLX3。基因表达、脑成像和胎儿脑表达数量性状基因座研究优先考虑 SLC35B1 和 PHB。这些分析表明，对复杂遗传疾病的单一遗传特征进行全基因组关联分析（GWAS），然后在相关组织中进行染色体构象研究，可以成功地揭示自闭症谱系障碍（ASD）单一核心特征的新风险基因。