Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, Wales.
Am J Psychiatry. 2013 Aug;170(8):877-85. doi: 10.1176/appi.ajp.2013.12020226.
OBJECTIVE The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure. METHOD A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide association studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNPs showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample. RESULTS Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume. CONCLUSIONS The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition.
目的 作者研究了最近确定的与精神分裂症相关的全基因组显著遗传风险变异对认知和大脑结构的影响。
方法 选择一组六个单核苷酸多态性（SNP）来代表来自三个最近的精神分裂症全基因组关联研究（GWAS）的全基因组显著位点，并在 346 名精神分裂症患者和 2342 名健康对照者中测试它们与认知测量的关联。对具有认知关联的显著结果进行了在独立病例对照样本中的复制评估。对于表现出与认知相关的关联的 SNP，在一个大型独立的健康对照样本中研究了与大脑结构体积的关联。
结果 六个 SNP 中有五个与任何认知测量均无显著关联。主要组织相容性复合体（MHC）区域的一个标记物 rs6904071 具有独立的、复制的与延迟情景记忆相关的证据，并且当两个样本合并时是显著的。在多达 3100 人的合并样本中，该 SNP 与认知领域的广泛影响相关，尽管在调整了延迟情景记忆后，这些额外的关联不再显著。在大型独立的结构成像样本中，同样的 SNP 也与海马体体积减小有关。
结论 作者确定了 MHC 区域中的一个 SNP，该 SNP 与精神分裂症患者和健康对照者的认知表现相关。该 SNP，rs6904071，与情景记忆和海马体体积有重复的关联。这些发现表明 MHC 区域与海马体结构和功能有关，这与 MHC 蛋白在突触发育和功能中的作用一致。对这些结果的后续研究有可能为精神分裂症和认知的病理生理学提供深入的了解。
