Chromatin interactions at risk loci links ATP5MD to schizophrenia

Genome-wide association studies (GWAS) have accelerated the discovery of numerous genetic variants associated with schizophrenia. However, most risk variants show a small effect size (odds ratio (OR)<1.2), suggesting that more functional risk variants remain to be identified. Here, we employed region-based multi-marker analysis of genomic annotation (MAGMA) to identify additional risk loci containing variants with large OR value from Psychiatry Genomics Consortium (PGC2) schizophrenia GWAS data and then employed summary-data-based mendelian randomization (SMR) to prioritize schizophrenia susceptibility genes. The top-ranked susceptibility gene ATP5MD, encoding an ATP synthase membrane subunit, is observed to be downregulated in schizophrenia by the risk allele of CNNM2-rs1926032 in the schizophrenia-associated 10q24.32 locus. Examination of chromatin interaction between rs1926032 and ATP5MD.

全基因组关联研究（Genome-wide association studies, GWAS）已极大加速了与精神分裂症相关的众多遗传变异的发现进程。然而，绝大多数风险变异的效应量较小（比值比（odds ratio, OR）<1.2），这意味着仍有更多具备功能效应的风险变异有待挖掘鉴定。本研究借助基于区域的多标记基因组注释分析（region-based multi-marker analysis of genomic annotation, MAGMA），从精神病学基因组学联盟（Psychiatry Genomics Consortium, PGC2）的精神分裂症GWAS数据中筛选出携带高OR值变异的新增风险位点；随后采用基于汇总数据的孟德尔随机化（summary-data-based mendelian randomization, SMR）方法对精神分裂症易感基因进行优先级排序。排名首位的易感基因ATP5MD可编码ATP合酶膜亚基，研究观察到其在精神分裂症患者体内会因精神分裂症关联的10q24.32位点上的CNNM2-rs1926032风险等位基因而出现表达下调。本研究同时对rs1926032与ATP5MD之间的染色质相互作用展开了检测分析。