Investigation of Rare Single-Nucleotide <i>PCDH15</i> Variants in Schizophrenia and Autism Spectrum Disorders

Both schizophrenia (SCZ) and autism spectrum disorders (ASD) are neuropsychiatric disorders with overlapping genetic etiology. Protocadherin 15 (PCDH15), which encodes a member of the cadherin super family that contributes to neural development and function, has been cited as a risk gene for neuropsychiatric disorders. Recently, rare variants of large effect have been paid attention to understand the etiopathology of these complex disorders. Thus, we evaluated the impacts of rare, single-nucleotide variants (SNVs) in PCDH15 on SCZ or ASD. First, we conducted coding exon-targeted resequencing of PCDH15 with next-generation sequencing technology in 562 Japanese patients (370 SCZ and 192 ASD) and detected 16 heterozygous SNVs. We then performed association analyses on 2,096 cases (1,714 SCZ and 382 ASD) and 1,917 controls with six novel variants of these 16 SNVs. Of these six variants, four (p.R219K, p.T281A, p.D642N, c.3010-1G>C) were ultra-rare variants (minor allele frequency < 0.0005) that may increase disease susceptibility. Finally, no statistically significant association between any of these rare, heterozygous PCDH15 point variants and SCZ or ASD was found. Our results suggest that a larger sample size of resequencing subjects is necessary to detect associations between rare PCDH15 variants and neuropsychiatric disorders.精神分裂症（schizophrenia, SCZ）与孤独症谱系障碍（autism spectrum disorders, ASD）均为存在重叠遗传病因的神经精神疾病。原钙粘蛋白15（Protocadherin 15, PCDH15）编码钙粘蛋白超家族成员，该家族参与神经发育与功能调控，此前被报道为神经精神疾病的风险基因。近年来，具有较大效应量的罕见变异成为解析这类复杂疾病发病机制的研究热点。因此，本研究探讨了PCDH15基因内罕见单核苷酸变异（single-nucleotide variants, SNVs）对SCZ或ASD发病的影响。首先，本研究采用下一代测序技术，对562名日本受试者（370名SCZ患者、192名ASD患者）的PCDH15基因编码外显子区域进行靶向重测序，共检出16个杂合单核苷酸变异。随后，针对该16个单核苷酸变异中的6个新变异，在2096例病例（1714例SCZ患者、382例ASD患者）与1917例对照人群中开展关联分析。上述6个变异中，4个（p.R219K、p.T281A、p.D642N、c.3010-1G>C）为超罕见变异（次要等位基因频率<0.0005），可能增加疾病易感风险。最终，本研究未发现任何上述杂合PCDH15点突变与SCZ或ASD存在统计学显著关联。本研究结果提示，需扩大重测序样本量，方能检测出PCDH15罕见变异与神经精神疾病之间的关联。