Blokland Gabriëlla A M, Wallace Angus K, Hansell Narelle K, Thompson Paul M, Hickie Ian B, Montgomery Grant W, Martin Nicholas G, McMahon Katie L, de Zubicaray Greig I, Wright Margaret J
QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, 300 Herston Road, Brisbane, QLD, 4006, Australia; Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD, 4072, Australia; School of Psychology, The University of Queensland, St Lucia, QLD, 4072, Australia.
QIMR Berghofer Medical Research Institute, Royal Brisbane and Women's Hospital, 300 Herston Road, Brisbane, QLD, 4006, Australia.
Int J Psychophysiol. 2017 May;115:98-111. doi: 10.1016/j.ijpsycho.2016.09.010. Epub 2016 Sep 23.
In a population-based genome-wide association (GWA) study of n-back working memory task-related brain activation, we extracted the average percent BOLD signal change (2-back minus 0-back) from 46 regions-of-interest (ROIs) in functional MRI scans from 863 healthy twins and siblings. ROIs were obtained by creating spheres around group random effects analysis local maxima, and by thresholding a voxel-based heritability map of working memory brain activation at 50%. Quality control for test-retest reliability and heritability of ROI measures yielded 20 reliable (r>0.7) and heritable (h>20%) ROIs. For GWA analysis, the cohort was divided into a discovery (n=679) and replication (n=97) sample. No variants survived the stringent multiple-testing-corrected genome-wide significance threshold (p<4.5×10), or were replicated (p<0.0016), but several genes were identified that are worthy of further investigation. A search of 529,379 genomic markers resulted in discovery of 31 independent single nucleotide polymorphisms (SNPs) associated with BOLD signal change at a discovery level of p<1×10. Two SNPs (rs7917410 and rs7672408) were associated at a significance level of p<1×10. Only one, most strongly affecting BOLD signal change in the left supramarginal gyrus (R=5.5%), had multiple SNPs associated at p<1×10 in linkage disequilibrium with it, all located in and around the BANK1 gene. BANK1 encodes a B-cell-specific scaffold protein and has been shown to negatively regulate CD40-mediated AKT activation. AKT is part of the dopamine-signaling pathway, suggesting a mechanism for the involvement of BANK1 in the BOLD response to working memory. Variants identified here may be relevant to (the susceptibility to) common disorders affecting brain function.
在一项基于人群的全基因组关联（GWA）研究中，我们对与n-back工作记忆任务相关的大脑激活情况进行了研究。该研究从863名健康双胞胎和兄弟姐妹的功能磁共振成像（fMRI）扫描中，提取了46个感兴趣区域（ROI）的平均BOLD信号变化百分比（2-back减去0-back）。ROI是通过在组随机效应分析局部最大值周围创建球体，并将工作记忆大脑激活的基于体素的遗传力图阈值设定为50%而获得的。对ROI测量的重测信度和遗传力进行质量控制后，得到了20个可靠（r>0.7）且可遗传（h>20%）的ROI。对于GWA分析，该队列被分为发现样本（n=679）和复制样本（n=97）。没有变体在经过严格的多重检验校正后达到全基因组显著性阈值（p<4.5×10），也没有被复制（p<0.0016），但确定了几个值得进一步研究的基因。对529,379个基因组标记的搜索，在发现水平p<1×10时，发现了31个与BOLD信号变化相关的独立单核苷酸多态性（SNP）。两个SNP（rs7917410和rs7672408）在显著性水平p<1×10时相关。只有一个SNP，对左侧缘上回的BOLD信号变化影响最大（R=5.5%），在连锁不平衡中有多个p<1×10的SNP与之相关，所有这些SNP都位于BANK1基因及其周围。BANK1编码一种B细胞特异性支架蛋白，已被证明对CD40介导的AKT激活具有负调控作用。AKT是多巴胺信号通路的一部分，这表明了BANK1参与对工作记忆的BOLD反应的一种机制。这里鉴定出的变体可能与影响脑功能的常见疾病（的易感性）相关。
