Abstract
Introduction: There is an unmet need to understand the genetic factors associated with stroke outcome. The purpose of this study is to identify the common genetic variants, if any, associated with incident of ischemic stroke in a community-based population and to determine if any genetic risk can be enriched in fatal stroke patients. Methods: Cases and controls of ischemic stroke were identified by leveraging the comprehensive Electronic Health Record, and endophenotypes, e.g. the fatal or nonfatal stroke was defined by those dying within one month (fatal incidence) or surviving to 12 months (nonfatal incidence) of their first-ever stroke incident. The GWAS was carried out in a nested case-control design by considering all patients with age >79 and without any stroke-related diagnostic codes as low-risk control. A linear mixed regression model (SAIGE) with saddlepoint approximation, adjusted for covariates was conducted to account for the relatedness and case-control imbalance. Results: No genome-wide significant association was identified for ischemic stroke (n=1,179) versus control (n=7,489). When stratifying stroke patients by the fatality (n=61/1,118), rs80094021 (MAF = 0.038; OR=3.332±0.635; p=9.04E-11) and SNPs in LD with, located at an intronic region of TIAM1, were the top associated signal. All these SNPs served as eQTL for TIAM1(β=0.144, p=5.8E-13, eQTLGen). Rs79694970, the second top SNP (MAF = 0.020; OR=4.179±0.931; p=9.27E-09), is located near GPD1L and functions as eQTL for GPD1L(β=-0.279, p=6.1E-28). GPD1L plays a role in the DPD1L-dependent SCN5A phosphorylation pathway, thereby regulating cardiac sodium current. Dysfunction of sodium current can cause fatal ventricular arrhythmia. According to PheWAS data from UK Biobank, rs80094021 showed a moderate association with high cholesterol (p=0.0045), coronary atherosclerosis (p=0.0075), and angina (p=0.012), with the same direction for the minor allele which increased the risk for fatal stroke. rs79694970 were associated with ischemic stroke (large artery atherosclerosis) with p=0.0016. Conclusion: Through stratification of ischemic stroke by fatality some genetic risk factors and genes with biological relevant to the pathogenesis of stroke could be identified.
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