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Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage

Jaeyoon Chung¹, Graham Hamilton¹, Minsup Kim¹

¹From the Center for Genomic Medicine (J.C., S.M., B.M., J.H., J.R., C.D.A.), Department of Neurology (B.M., J.H., S.M.G., A.V., J.R., C.D.A.), McCance Center for Brain Health (J.H., J.R., C.D.A.), and Department of Emergency Medicine (J.N.G.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (J.C., J.R., C.D.A.), Broad Institute, Boston, MA; Glasgow Polyomics, Wolfson Wohl Cancer Research Centre, Garscube Campus (G.H.), and Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences (G.H., T.V.A.), University of Glasgow, Bearsden, UK; Department of Bioinformatics (M.K., A.E.C.), Korea University, Sejong, South Korea; Stroke Program, Department of Neurology (D.L.B.), University of Michigan, Ann Arbor; Department of Neurology and Public Health Sciences (B.B.W.), University of Virginia Health System, Charlottesville; Department of Neurology (J.F.M.), Mayo Clinic Jacksonville; Department of Neurology (S.L.S.), University of Florida College of Medicine, Jacksonville; Department of Neurology, Stroke Division (M.S.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Neurology, Harborview Medical Center (D.L.T.), University of Washington, Seattle; Department of Neurology (C.S.K.), The University of Arizona, Tucson; Department of Neurology and Rehabilitation Medicine (B.K., D.W.), University of Cincinnati, OH; Center for Public Health Genomics and Department of Biostatistical Sciences (C.D.L.), Wake Forest School of Medicine, Winston-Salem, NC; Centre for Medical Informatics, Usher Institute (K.R., C.L.M.S.), Centre for Clinical Brain Sciences (N.S., M.R., R.A.-S.S.), The Roslin Institute (J.G.D.P.), and Lothian Birth Cohorts Group, Department of Psychology (S.E.H., I.D.), University of Edinburgh; and British Heart Foundation Data Science Centre (K.R.), London, UK. Dr. Anderson is currently at the Department of Neurology, Brigham and Women's Hospital, Boston, MA.

|May 25, 2021

Abstract

Objective:

To test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH.

Methods:

We performed sequencing across 559 Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in United States-based and 1,381 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling.

Results:

We identified 107 rare nonsynonymous variants in sporadic ICH, of which 2 missense variants, rs138269346 (COL4A1^I110T) and rs201716258 (COL4A2^H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the United States-based cohort. The minor allele of rs201716258 was also present in Scottish patients with ICH, and rs138269346 was observed in 2 ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with nonlobar ICH risk (p = 0.05), but not with lobar ICH (p = 0.08), while associations between rs201716258 and ICH subtypes were nonsignificant (p > 0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in European populations), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen).

Conclusions:

We identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.

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