Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, 315211, Zhejiang, China.
School of Basic Medical Science, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, 315211, Zhejiang, China.
Cereb Cortex. 2023 May 24;33(11):6990-7000. doi: 10.1093/cercor/bhad014.
Patients with bipolar disorder (BD) and their first-degree relatives exhibit alterations in brain volume and cortical structure, whereas the underlying genetic mechanisms remain unclear. In this study, based on the published genome-wide association studies (GWAS), the extent of polygenic overlap between BD and 15 brain structural phenotypes was investigated using linkage disequilibrium score regression and MiXeR tool, and the shared genomic loci were discovered by conjunctional false discovery rate (conjFDR) and expression quantitative trait loci (eQTL) analyses. MiXeR estimated the overall measure of polygenic overlap between BD and brain structural phenotypes as 4-53% on a 0-100% scale (as quantified by the Dice coefficient). Subsequent conjFDR analyses identified 54 independent loci (71 risk single-nucleotide polymorphisms) jointly associated with BD and brain structural phenotypes with a conjFDR < 0.05, among which 33 were novel that had not been reported in the previous BD GWAS. Follow-up eQTL analyses in respective brain regions both confirmed well-known risk genes (e.g. CACNA1C, NEK4, GNL3, MAPK3) and discovered novel risk genes (e.g. LIMK2 and CAMK2N2). This study indicates a substantial shared genetic basis between BD and brain structural phenotypes, and provides novel insights into the developmental origin of BD and related biological mechanisms.
双相情感障碍（BD）患者及其一级亲属的大脑体积和皮质结构存在改变，而潜在的遗传机制尚不清楚。在这项研究中，基于已发表的全基因组关联研究（GWAS），使用连锁不平衡评分回归和 MiXeR 工具研究了 BD 与 15 种脑结构表型之间的多基因重叠程度，并通过联合假发现率（conjFDR）和表达数量性状基因座（eQTL）分析发现了共享的基因组位点。MiXeR 估计 BD 和脑结构表型之间的多基因重叠的总体程度为 0-100%范围内的 4-53%（通过 Dice 系数量化）。随后的 conjFDR 分析确定了 54 个独立的位点（71 个风险单核苷酸多态性），它们与 BD 和脑结构表型共同相关，conjFDR<0.05，其中 33 个是以前的 BD GWAS 中未报道的新风险单核苷酸多态性。在各自的脑区进行的后续 eQTL 分析均证实了众所周知的风险基因（如 CACNA1C、NEK4、GNL3、MAPK3），并发现了新的风险基因（如 LIMK2 和 CAMK2N2）。这项研究表明 BD 和脑结构表型之间存在大量的共同遗传基础，并为 BD 的发育起源和相关生物学机制提供了新的见解。
