Stroke genetics informs drug discovery and risk prediction across ancestries

Abstract

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Early peripheral blood gene expression associated with good and poor 90-day ischemic stroke outcomes

“…We found several genes differentially expressed in our analysis associated with stroke outcome that have also been found in genome-wide association studies (GWAS) to be significant stroke risk loci. For example, variants rs12579302, rs10886430, rs55983834, rs2501966, rs12426667 are stroke risk loci in differentially expressed stroke outcome genes ATP2B , GRK5 , SH3PXD2A , CENPQ , HOXC4 , respectively; and intergenic variants rs2107595 and rs1487504 are stroke risk loci in differentially expressed outcome genes HDAC9 and BNC2 , respectively [ 55 ]. In addition, the genome-wide significant stroke risk locus rs7974266 was upstream of differentially expressed gene PTPN11 , rs12539561 was downstream of differentially expressed gene PIK3CG , and the 3-prime UTR variant rs42035 was downstream of differentially expressed outcome gene CDK6 [ 55 ].…”

“…For example, variants rs12579302, rs10886430, rs55983834, rs2501966, rs12426667 are stroke risk loci in differentially expressed stroke outcome genes ATP2B , GRK5 , SH3PXD2A , CENPQ , HOXC4 , respectively; and intergenic variants rs2107595 and rs1487504 are stroke risk loci in differentially expressed outcome genes HDAC9 and BNC2 , respectively [ 55 ]. In addition, the genome-wide significant stroke risk locus rs7974266 was upstream of differentially expressed gene PTPN11 , rs12539561 was downstream of differentially expressed gene PIK3CG , and the 3-prime UTR variant rs42035 was downstream of differentially expressed outcome gene CDK6 [ 55 ]. Another GWAS significant protein-coding variant (rs1778155) in the PDE4DIP gene was associated with an increased risk of stroke [ 56 ] and in our data PDE4DIP was up-regulated in participants with poor vs good outcome.…”

A genetic risk score improves risk stratification for anticoagulation-related intracerebral hemorrhage

“…Larger GWAS could provide a more robust and generalizable GRS, but due to the rarity of ICH, GWAS efforts have been slower than for ischemic stroke. 23,40 Despite these challenges, our results demonstrate that in a score of eight different clinical risk factors for major hemorrhage, one additional point for the highest genetic ICH risk substantially improves the prediction of incident ICH. Thus, in situations with clinical equipoise, we submit that individual genetic ICH risk could be accounted for when stratifying an individual both for ICH and major hemorrhage risk.…”

Exome Array Analysis of 9,721 ischemic stroke cases from the SiGN Consortium

“…1 The etiology of ischemic stroke, the predominant form of stroke, is multifactorial and includes both genetic and nongenetic causes. Genome-wide association studies (GWAS) have identified 89 stroke-associated loci to date 2; 3 , although these loci account for only a very small proportion of stroke heritability. A major limitation of current genome-wide approaches, which rely predominantly on genotyping arrays, is that they typically interrogate only common variation throughout the genome (eg, SNPs with minor allele frequency > 1-5%) and generally do not cover the coding regions of the genome.…”