Han Shengtong
School of Dentistry, Marquette University, Milwaukee, WI 53201-1881, USA.
J Pers Med. 2024 Aug 2;14(8):822. doi: 10.3390/jpm14080822.
The genetics of schizophrenia is so complex that it involves both common variants and rare variants. Rare variant association studies of schizophrenia are challenging because statistical methods for rare variant analysis are under-powered due to the rarity of rare variants. The recent Schizophrenia Exome meta-analysis (SCHEMA) consortium, the largest consortium in this field to date, has successfully identified 10 schizophrenia risk genes from ultra-rare variants by burden test, while more risk genes remain to be discovered by more powerful rare variant association test methods. In this study, we use a recently developed Bayesian rare variant association method that is powerful for detecting sparse rare risk variants that implicates 88 new candidate risk genes associated with schizophrenia from the SCHEMA case-control sample. These newly identified genes are significantly enriched in autism risk genes and GO enrichment analysis indicates that new candidate risk genes are involved in mechanosensory behavior, regulation of cell size, neuron projection morphogenesis, and plasma-membrane-bounded cell projection morphogenesis, that may provide new insights on the etiology of schizophrenia.
精神分裂症的遗传学非常复杂，涉及常见变异和罕见变异。精神分裂症的罕见变异关联研究具有挑战性，因为由于罕见变异的稀缺性，用于罕见变异分析的统计方法效力不足。最近的精神分裂症外显子荟萃分析（SCHEMA）联盟是该领域迄今为止最大的联盟，通过负担测试已成功从超罕见变异中鉴定出10个精神分裂症风险基因，而更多的风险基因仍有待通过更强大的罕见变异关联测试方法来发现。在本研究中，我们使用了一种最近开发的贝叶斯罕见变异关联方法，该方法对于检测稀疏的罕见风险变异很有效，从SCHEMA病例对照样本中鉴定出88个与精神分裂症相关的新候选风险基因。这些新鉴定的基因在自闭症风险基因中显著富集，基因本体（GO）富集分析表明新候选风险基因参与机械感觉行为、细胞大小调节、神经元投射形态发生和质膜结合的细胞投射形态发生，这可能为精神分裂症的病因学提供新的见解。
