Meta-analysis of Genome-wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

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

“…A notable finding was the identification of PMF1-SEMA4A as a risk locus for AIS. PMF1–SEMA4A is an established risk locus for nonlobar ICH 6 and thus is, to our knowledge, the first reported locus reaching genome-wide significance for ischemic as well as hemorrhagic stroke. PMF1–SEMA4A further reached genome-wide association for WMH burden 28 (Fig.…”

“…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 . We hypothesized that combining a substantially larger sample size with a transancestral analytic approach would identify additional risk loci and improve fine mapping of causal variants.…”

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

“…We explore the implications of these associations for the clinician in terms of predictive testing, therapeutic potential, and the impact on clinical management, as well as the insights into stroke pathophysiology, and consider aspects that need to be addressed in future studies to maximize the potential of GWASs. This Review focuses on findings in ischaemic stroke, although advances are also being made in intracerebral haemorrhage, 12 including the genetics of intracranial aneurysms. 13 …”

Recommendations From the International Stroke Genetics Consortium, Part 2

“…Challenges include inability to modify sample or data collection and handling at local sites, and ethical considerations when data and samples were collected some time ago and new uses may be different than what was originally approved by local ethics committees. Studies that have employed this strategy are the ISGC-Wellcome Trust Case Control Consortium 2 Genome-Wide Association Study 5 , the National Institute of Neurological Disorders Ischemic Stroke Genetics Network (NINDS-SiGN) 6 , and the ISGC’s genome-wide association study of intracerebral hemorrhage 7 .…”