Ueno Fumihiko, Takahashi Ippei, Ohseto Hisashi, Onuma Tomomi, Narita Akira, Obara Taku, Ishikuro Mami, Murakami Keiko, Noda Aoi, Matsuzaki Fumiko, Metoki Hirohito, Tamiya Gen, Kure Shigeo, Kuriyama Shinichi
Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
Graduate School of Medicine, Tohoku University, Sendai, Japan.
PLoS One. 2025 May 29;20(5):e0322698. doi: 10.1371/journal.pone.0322698. eCollection 2025.
Autism spectrum disorder (ASD) presents with heterogeneous phenotypic and genetic characteristics. Despite investigation into the molecular mechanisms underlying ASD, its etiology remains elusive. In our previous investigation within the Simons Simplex Collection (SSC), we noted increased signals through a genome-wide association study (GWAS) by clustering patients with ASD and reducing the sample size. This study seeks to validate our previous study in a different population, the Simons Foundation Powering Autism Research for Knowledge (SPARK) population, while probing further into the genetic architecture of ASD. We examined data from 2,079 white male subjects and 875 unaffected SPARK siblings. Our methodology encompassed cluster analyses, followed by traditional GWAS and cluster-based GWAS (cGWAS). No significant associations were observed in the conventional GWAS when comparing all patients with all controls. However, in the cGWAS, by comparing patients clustered by phenotypes with controls, we identified 27 chromosomal loci meeting the criteria of p < 5.0 × 10 ⁻ 8. Remarkably, several of these loci were situated within or in proximity to genes previously implicated as candidates for ASD. Nonetheless, our previous study of the SSC population did not fully replicate the SPARK population. The absence of reproducibility suggests the possibility of false positives within the cGWAS results due to potential technical factors. However, the emergence of multiple signals post-clustering and the association of numerous identified gene regions with ASD and related disorders provide supporting evidence for the validity of cGWAS outcomes.
自闭症谱系障碍（ASD）具有异质性的表型和遗传特征。尽管对ASD潜在的分子机制进行了研究，但其病因仍不明确。在我们之前对西蒙斯单基因队列（SSC）的研究中，我们通过对ASD患者进行聚类并减少样本量，在全基因组关联研究（GWAS）中发现了增强的信号。本研究旨在在不同人群——西蒙斯基金会助力自闭症研究知识计划（SPARK）人群中验证我们之前的研究，同时进一步探究ASD的遗传结构。我们检查了来自2079名白人男性受试者和875名未受影响的SPARK同胞的数据。我们的方法包括聚类分析，随后进行传统的GWAS和基于聚类的GWAS（cGWAS）。在将所有患者与所有对照进行比较时，传统GWAS未观察到显著关联。然而，在cGWAS中，通过将按表型聚类的患者与对照进行比较，我们确定了27个符合p < 5.0×10⁻⁸标准的染色体位点。值得注意的是，其中几个位点位于先前被认为是ASD候选基因之内或附近。尽管如此，我们之前对SSC人群的研究并未完全在SPARK人群中得到重复。缺乏可重复性表明由于潜在的技术因素，cGWAS结果中可能存在假阳性。然而，聚类后出现的多个信号以及众多已识别基因区域与ASD及相关疾病的关联为cGWAS结果的有效性提供了支持证据。
