A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype

Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75×10−6 and 8.3×10−7. Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders.精神分裂症患者及其同胞通常会出现大脑结构的细微改变，例如海马体积（hippocampal volume）减小。海马体积（hippocampal volume）具有可遗传性，可解释精神分裂症的多种认知症状，因此被视为该精神疾病的中间表型（intermediate phenotype）。本研究的分析目标为：在无需预先设定潜在候选基因的前提下，鉴定与海马体积相关的单核苷酸多态性（single-nucleotide polymorphisms, SNP）。本研究整合了来自精神分裂症Mind临床成像联盟（Mind Clinical Imaging Consortium）研究的遗传学、影像学及神经心理学数据，共纳入328名受试者。通过全基因组关联研究（genome-wide association study, GWAS），本研究共对743,591个SNP开展了海马体积关联分析。我们针对显著关联SNP的所在基因区域，分析了人类海马组织的基因表达谱。未发现任何遗传标记达到全基因组显著性水平。然而，位于19号染色体19p13.11区域、紧邻或位于NR2F6、USHBP1及BABAM1基因内或其邻近区域的6个高度相关SNP（rs4808611、rs35686037、rs12982178、rs1042178、rs10406920、rs8170），以及另外3个基因组区域（1号、2号及10号染色体）内的4个SNP，其P值介于6.75×10⁻⁶至8.3×10⁻⁷之间。借助近期发表的海马体积全基因组关联研究现有数据，以及针对欧洲血统青少年大型队列的多中心研究补充数据，本研究结果获得了验证支持。此外，rs4808611与rs8170的等位基因差异，与顺式作用区域（cis-acting）内的差异mRNA表达显著相关。与记忆功能的关联提示，本研究鉴定出的风险变异可能具有重要的功能意义。本研究的发现为与精神分裂症密切相关的大脑结构的遗传架构提供了新见解。计算机模拟（in silico）验证、mRNA表达及认知数据进一步支持了本研究结果的相关性。鉴定因果变异及其功能效应，或可揭示神经发育及神经精神疾病发病机制中尚未被发现的关键调控因子。