Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Department of Neurology, the 3rd Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China.
BMC Med. 2022 Jun 23;20(1):211. doi: 10.1186/s12916-022-02408-y.
Previous genome-wide association studies (GWAS) have identified numerous risk genes for lacunar stroke, but it is challenging to decipher how they confer risk for the disease. We employed an integrative analytical pipeline to efficiently transform genetic associations to identify novel proteins for lacunar stroke.
We systematically integrated lacunar stroke genome-wide association study (GWAS) (N=7338) with human brain proteomes (N=376) to perform proteome-wide association studies (PWAS), Mendelian randomization (MR), and Bayesian colocalization. We also used an independent human brain proteomic dataset (N=152) to annotate the new genes.
We found that the protein abundance of seven genes (ICA1L, CAND2, ALDH2, MADD, MRVI1, CSPG4, and PTPN11) in the brain was associated with lacunar stroke. These seven genes were mainly expressed on the surface of glutamatergic neurons, GABAergic neurons, and astrocytes. Three genes (ICA1L, CAND2, ALDH2) were causal in lacunar stroke (P < 0.05/proteins identified for PWAS; posterior probability of hypothesis 4 ≥ 75 % for Bayesian colocalization), and they were linked with lacunar stroke in confirmatory PWAS and independent MR. We also found that ICA1L is related to lacunar stroke at the brain transcriptome level.
Our present proteomic findings have identified ICA1L, CAND2, and ALDH2 as compelling genes that may give key hints for future functional research and possible therapeutic targets for lacunar stroke.
先前的全基因组关联研究（GWAS）已经确定了许多腔隙性卒中的风险基因，但要破译它们如何为疾病带来风险具有挑战性。我们采用了一种综合分析管道，以有效地将遗传关联转化为识别腔隙性卒中的新蛋白质。
我们系统地整合了腔隙性卒中全基因组关联研究（GWAS）（N=7338）与人类大脑蛋白质组（N=376），以进行蛋白质组关联研究（PWAS）、孟德尔随机化（MR）和贝叶斯共定位分析。我们还使用了一个独立的人类大脑蛋白质组数据集（N=152）来注释新基因。
我们发现大脑中七种基因（ICA1L、CAND2、ALDH2、MADD、MRVI1、CSPG4 和 PTPN11）的蛋白质丰度与腔隙性卒中相关。这七个基因主要在谷氨酸能神经元、GABA 能神经元和星形胶质细胞的表面表达。其中三个基因（ICA1L、CAND2、ALDH2）在腔隙性卒中中有因果关系（PWAS 中鉴定的蛋白质 P<0.05/个；贝叶斯共定位的假设 4 的后验概率≥75%），并在确认性 PWAS 和独立 MR 中与腔隙性卒中相关。我们还发现 ICA1L 与腔隙性卒中在大脑转录组水平上有关。
我们目前的蛋白质组学发现确定了 ICA1L、CAND2 和 ALDH2 作为有说服力的基因，这些基因可能为未来的功能研究提供关键线索，并为腔隙性卒中提供可能的治疗靶点。
