Fig. 1: ExWAS identifies NOTCH3 p.Arg1231Cys associated with subcortical hemorrhagic stroke in Pakistan genome resource 31 K discovery cohort.
From: NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke
A Flow chart of the study described in this report. The discovery cohort consisted of a 31 K stroke case-control cohort (n = 31,737, including n = 5135 stroke cases and n = 26,602 controls) from the Pakistan Genome Resource (PGR) (green boxes). A second PGR follow-up cohort of 44 K (n = 44,082) included 30 K participants with self-reported stroke case:control status for replication (n = 30,399, including n = 160 cases and n = 30,239 controls). UK Biobank data from 450 K sequenced participants was used for further analysis in a predominantly European ancestry population (blue boxes), 380 K of whom had stroke case:control status known (n = 9143 cases and n = 371,403 controls), and 35 K of whom had brain MRI data (n = 35,344). B Manhattan plot of subcortical hemorrhagic stroke ExWAS in PGR discovery cohort participants (n = 1388 hemorrhagic stroke cases and n = 26,602 controls) with likelihood ratio test -log10 p-values of calculated using REGENIE (y-axis) across chromosomes (alternating gray and black dots) and variants (x-axis). A single variant (NC_000019.10:g.15179052 G > A) on chromosome 19 predicting a missense variant p.Arg1231Cys in NOTCH3 (pink diamond) exceeded the genome-wide significance threshold of 5 × 10−8 (red line). C. NOTCH3 locus zoom plot of subcortical stroke ExWAS. The likelihood ratio test -log10 p values for variants tested are shown on the y-axis. The p.Arg1231Cys variant is labeled as a diamond. Other variants (circles) are colored based on linkage disequilibrium with the reference variant in 1000 Genomes38. Gene exon (thick line) and intron (thin line) model shown below the graph.
