Identification of novel proteins for lacunar stroke by integrating genome-wide association data and human brain proteomes

• Published in: BMC medicine Vol. 20; no. 1; pp. 1 - 11
• Main Authors: Zhang, Chengcheng, Qin, Fengqin, Li, Xiaojing, Du, Xiangdong, Li, Tao
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 23.06.2022; BioMed Central; BMC
• Subjects: Aldehyde dehydrogenase; ALDH2; Alzheimer's disease; Astrocytes; Bayesian analysis; Biological markers; Biomarkers; Brain; Brain research; CAND2; Conditional probability; Consortia; Functional genomics; Gene expression; Genes; Genetic aspects; Genome-wide association studies; Genomes; Genomics; Glutamatergic transmission; Health aspects; Health risks; Human brain proteomes; Hypotheses; ICA1L; Identification and classification; Lacunar stroke; Magnetic resonance imaging; Methods; Neurons; Peptides; Proteins; Proteomes; Proteomics; Quality control; Risk factors; Stroke; Stroke (Disease); Therapeutic targets; Transcriptomes; γ-Aminobutyric acid; China; United Kingdom > UK
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-022-02408-y

Background 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. Methods 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. Results 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 [greater than or equai to] 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. Conclusions 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. Keywords: Lacunar stroke, Human brain proteomes, Functional genomics, ICA1L, CAND2, ALDH2