Association of SUMOylation Pathway Genes With Stroke in a Genome-Wide Association Study in India

Abstract

Objective:To undertake a genomewide association study (GWAS) to identify genetic variants for stroke in Indians.Methods:In a hospital-based case-control study, eight teaching hospitals in India recruited 4,088 subjects, including 1,609 stroke cases. Imputed genetic variants were tested for association with stroke subtypes using both single-marker and gene-based tests. Association with vascular risk factors was performed using logistic regression. Various databases were searched for replication, functional annotation, and association with related traits. Status of candidate genes previously reported in the Indian population was also checked.Results:Association of vascular risk factors with stroke were similar to previous reports, and show modifiable risk factors like hypertension, smoking, and alcohol consumption having the highest effect. Single-marker based association revealed two loci for cardioembolic stroke (1p21 and 16q24), two for small vessel disease stroke (3p26 and 16p13), and four for hemorrhagic stroke (3q24, 5q33, 6q13, and 19q13) at P<5×10-8. The index SNP of 1p21 is an eQTL (Plowest=1.74×10-58) for RWDD3 involved in SUMOlation and is associated with platelet distribution width (1.15×10-9) and 18-carbon fatty acid metabolism (P=7.36×10-12). In gene-based analysis we identified three genes (SLC17A2, FAM73A and OR52L1) at P<2.7×10-6. 11 of 32 candidate gene loci studied in Indians replicated (P<0.05), and 21 of 32 loci identified through previous GWAS replicated based on directionality of effect.Conclusions:This first GWAS of stroke in Indians identified novel loci and replicated previously known loci. For the first time, genetic variants in the SUMOlation pathway which has been implicated in brain ischemia were identified.

Impact of RSUME Actions on Biomolecular Modifications in Physio-Pathological Processes

“…Enhanced SUMOylation has been proposed to protect from stroke and ischemia of the brain ( 20 , 21 ). In line with this, RSUME has been associated with cardioembolic stroke in an Indian stroke patient´s study ( 19 ). Interestingly, in this GWAS study, the authors discovered loci related to different stroke types and located close to certain genes, where RWDD3 is one of them.…”

“…Similarly, the previously described GWAS study that associates an SNP affecting an RSUME’s QTL with cardioembolic stroke ( 19 ) provides a novel view for the hypoxia-mediated regulation of RSUME expression in cardiac tissue. Moreover, a different study found a suggestive locus near the RSUME gene that is involved in inter-individual levels of the Proprotein convertase subtilisin/kexin type 9 (PCSK9), which is a regulator of LDL receptor degradation and is associated with cardiovascular risk ( 45 ).…”

“…Besides its role in tumor progression, recent studies reveal that RSUME is connected with cardiac tissue response to ischemia and stroke ( 18 , 19 ) ( Figure 2 ). Enhanced SUMOylation has been proposed to protect from stroke and ischemia of the brain ( 20 , 21 ).…”

“…Interestingly, in this GWAS study, the authors discovered loci related to different stroke types and located close to certain genes, where RWDD3 is one of them. Further analysis revealed that this locus is an expression quantitative trait locus (eQTL) for RSUME and also associated with platelet distribution width and lipid metabolism ( 19 ), suggesting that RSUME expression levels are tightly regulated in stroke. This finding points RSUME level as an important factor to the proper response of cardiac tissue.…”

Grand challenges in stroke genomics

“…Most stroke risk loci known to date have been identified in populations of European ancestry. With few exceptions (Keene et al, 2020;Kumar et al, 2021), populations of African, Hispanic, and South-Asian ancestry who bear the largest burden of stroke worldwide are underrepresented in current GWAS. There are both scientific and ethical arguments to support the need for greater diversity in stroke genomic studies.…”