O'Connell Kevin S, Sønderby Ida E, Frei Oleksandr, van der Meer Dennis, Athanasiu Lavinia, Smeland Olav B, Alnæs Dag, Kaufmann Tobias, Westlye Lars T, Steen Vidar M, Andreassen Ole A, Hughes Timothy, Djurovic Srdjan
NORMENT, Institute of Clinical Medicine, University of Oslo, & Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Psychol Med. 2021 Mar 3;52(15):1-11. doi: 10.1017/S0033291721000179.
Abstract.
Altered expression of the complement component C4A gene is a known risk factor for schizophrenia. Further, predicted brain C4A expression has also been associated with memory function highlighting that altered C4A expression in the brain may be relevant for cognitive and behavioral traits.
We obtained genetic information and performance measures on seven cognitive tasks for up to 329 773 individuals from the UK Biobank, as well as brain imaging data for a subset of 33 003 participants. Direct genotypes for variants (n = 3213) within the major histocompatibility complex region were used to impute C4 structural variation, from which predicted expression of the C4A and C4B genes in human brain tissue were predicted. We investigated if predicted brain C4A or C4B expression were associated with cognitive performance and brain imaging measures using linear regression analyses.
We identified significant negative associations between predicted C4A expression and performance on select cognitive tests, and significant associations with MRI-based cortical thickness and surface area in select regions. Finally, we observed significant inconsistent partial mediation of the effects of predicted C4A expression on cognitive performance, by specific brain structure measures.
These results demonstrate that the C4 risk locus is associated with the central endophenotypes of cognitive performance and brain morphology, even when considered independently of other genetic risk factors and in individuals without mental or neurological disorders.
摘要。
补体成分C4A基因表达改变是精神分裂症的已知风险因素。此外，预测的脑C4A表达也与记忆功能相关，这突出表明脑中C4A表达改变可能与认知和行为特征有关。
我们从英国生物银行获取了多达329773人的七个认知任务的遗传信息和表现测量数据，以及33003名参与者子集的脑成像数据。使用主要组织相容性复合体区域内变异（n = 3213）的直接基因型来推断C4结构变异，由此预测人脑组织中C4A和C4B基因的表达。我们使用线性回归分析研究预测的脑C4A或C4B表达是否与认知表现和脑成像测量相关。
我们发现预测的C4A表达与特定认知测试的表现之间存在显著负相关，并且与特定区域基于MRI的皮质厚度和表面积存在显著相关。最后，我们观察到特定脑结构测量对预测的C4A表达对认知表现的影响存在显著不一致的部分中介作用。
这些结果表明，即使独立于其他遗传风险因素并在没有精神或神经疾病的个体中考虑，C4风险基因座也与认知表现和脑形态的中枢内表型相关。
