Association of SUMOlation pathway genes with stroke in a genome-wide association study in India

Objective: To undertake a genome-wide 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 &
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.