Genetic variation at 16q24.2 is associated with small vessel stroke

Abstract

Objective Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises a quarter of all ischaemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown younger onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger onset SVS population, to identify novel associations with stroke. Methods We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on mRNA expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (OR(95% CI)=1.16(1.10–1.22); p=3.2×10−9). The lead SNP (rs12445022) was also associated with cerebral white matter hyperintensities (OR(95% CI)=1.10(1.05–1.16); p=5.3×10−5; N=3,670), but not intracerebral haemorrhage (OR(95% CI)=0.97(0.84–1.12); p=0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p=9.4×10−7), and DNA methylation at probe cg16596957 in whole blood (p=5.3×10−6). Interpretation 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements.

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

“…Common etiological subtypes of ischemic stroke include large-artery atherosclerotic stroke (LAS), cardioembolic stroke (CES), and stroke caused by small-vessel disease (small-vessel stroke (SVS)), which is also the leading cause of ICH. Previous genome-wide association studies (GWAS) in predominantly European-ancestry groups have identified ten loci robustly associated with stroke 3–12 . In most instances, the associations with stroke were attributed to individual subtypes of ischemic stroke, such as LAS 5,8,9 , CES 3,4 , and SVS 10,12 , or of ICH 6 , although some loci were associated with two or more stroke subtypes 7,9,11,13 or with any stroke 10 .…”

A large population-based investigation into the genetics of susceptibility to gastrointestinal infections and the link between gastrointestinal infections and mental illness

“…This SNP has previously been found to be associated with immune markers such as myeloid white cell/ neutrophil count (Astle et al 2016), as well as with tonsillectomy (Pickrell et al 2016). Furthermore, the same SNP has been associated with conditions such as coronary artery disease (Pickrell et al 2016), shown suggestive association to ischemic stroke (Traylor et al 2017), and been connected to metabolic traits such as fasting glucose levels (Wessel et al 2015). Some of these traits, namely the immune markers, are related to infection and could potentially be on some pathway together with the infection phenotype in our study.…”

Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities

“…Our meta-analysis discovered a high number of significant SNPs, genes and loci that are only associated with PVWMH, more than any single total WMH GWAS to date. Most genes and loci previously reported as significant in total WMH 29,30,32,37,39 were found to be associated with PVWMH alone, including PLEKHG1 29 , SH3PXD2A 17,41,48 and COL4A2 48 . Most of the genes associated with PVWMH have direct effects on vascular function, or with vascular diseases such as ischemic stroke, intracranial hemorrhage or coronary artery disease.…”