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

Abstract

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 ≥ 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.

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“…This is as a highly plausible prioritized gene that is likely to modulate the metabolism of amyloid precursor protein (APP) (23) and increase risk of AD. ICA1L encodes a protein whose expression is activated by type IV collagen and plays a crucial role in myelination (46). Increased ICA1L expression is also associated with lower risk of AD (47)(48)(49) and small vessel strokes (SVS), the acute outcomes of cerebral SVD, which may lead to VaD (50).…”

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“…Cis‐regulated brain protein levels of the PTPN11 gene are associated with lacunar stroke, and this gene is expressed on the surface of glutaminergic neurons, aminobutyric acid neurons, and astrocytes (Zhang et al, 2022). Lacunar cerebral infarction is mainly caused by AS and the occlusion of small perforated arteries caused by long‐term hypertension, diabetes, and other risk factors.…”

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