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Neurology. 2017 Oct 24;89(17):1829-1839. doi: 10.1212/WNL.0000000000004560. Epub 2017 Sep 27.

COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls.

Collaborators (233)

McArdle PF, Wong Q, Gwinn K, Achterberg S, Algra A, Amouyel P, Arnett DK, Arsava EM, Attia J, Ay H, Bartz TM, Battey T, Benavente OR, Bevan S, Biffi A, Bis JC, Blanton SH, P J, Boncoraglio GB, Brown RD Jr, Burgess AI, Carrera C, Chapman Smith SN, Chasman DI, Chauhan G, Wei-Min Chen F, Cheng YC, Cloonan LK, Cole JW, Cotlarciuc I, Cruchaga C, Cuadrado-Godia E, Dawson J, Debette S, Delavaran H, Dell CA, Doheny KF, Dong C, Duggan DJ, Engström G, Evans MK, Pallejà XE, Faul JD, Fornage M, Frossard PM, Furie K, Gamble DM, Gieger C, Giese AK, Giralt-Steinhauer E, González HM, Goris A, Gretarsdottir S, Grewal RP, Grittner U, Gustafsson S, Han B, Hankey GJ, Heitsch L, Higgins P, Hochberg MC, Holliday E, Hopewell JC, Horenstein RB, Howard G, Ikram MA, Ilinca A, Ingelsson E, Irvin MR, Jackson RD, Jern C, Johnson JA, Jood K, Kahn MS, Kaplan R, Kappelle LJ, Kardia SL, Keene KL, Kissela BM, Kleindorfer DO, Koblar S, Labovitz D, Launer LJ, Laurie CC, Laurie CA, Lee CH, Lee JM, Lemmens R, Levi C, Leys D, Longstreth WT Jr, Maguire J, Manichaikul A, McClure LA, McDonough CW, Meisinger C, Melander O, Meschia JF, Mola-Caminal M, Mosley TH, Müller-Nurasyid M, Nalls MA, O'Connell JR, Ois Á, Papanicolaou GJ, Peddareddygari LR, Pedersén A, Pera J, Peters A, Poole D, Psaty BM, Rabionet R, Raffeld MR, Rasheed A, Redfors P, Reiner AP, Rexrode K, Ribasés M, Rich SS, Robberecht W, Rodríguez-Campello A, Rolfs A, Roquer J, Rose LM, Rosenbaum D, Rost NS, Rothwell PM, Rundek T, Ryan KA, Sacco RL, Sale MM, Saleheen D, Salomaa V, Sánchez-Mora C, Schmidt CO, Schmidt H, Schmidt R, Schürks M, Scott R, Segal HC, Seiler S, Sharma P, Shuldiner AR, Silver B, Smith JA, Bsc CS, Sparks MJ, Stanne T, Stefansson K, Stine OC, Strauch K, Sturm J, Tajuddin SM, Talbert RL, Tatlisumak T, Thijs V, Thorleifsson G, Thorsteindottir U, Trompet S, Valant V, Waldenberger M, Walters M, Wang L, P J, Wang XQ, Wassertheil-Smoller S, Weir DR, Wiggins KL, Williams SR, Wloch-Kopec D, Woodfield R, Wu O, Xu H, Zonderman AB, de Bakker PIW, Kittner SJ, Bevan S, Hopewell JC, Holliday EG, Zhao W, Abrantes P, Amouyel P, Attia JR, Battey TW, Berger K, Boncoraglio GB, Chauhan G, Cheng YC, Chen WM, Clarke R, Cotlarciuc I, Debette S, Ferro JM, Gamble DM, Ilinca A, Kittner SJ, Lemmens R, Levi CR, Lichtner P, Liu J, Meschia JF, Oliveira SA, Pera J, Reiner AP, Rothwell PM, Sharma P, Tatlisumak T, Thijs V, Vicente AM, Saleheen D, Thorsteinsdottir U, DeStefano AL, Gretarsdottir S, Donnelly P, Barroso I, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Deloukas P, Duncanson A, Jankowski J, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood NW, Spencer CC.

Author information

1
From the Centre for Clinical Brain Sciences (K.R., C.L.M.S.), College of Medicine and Veterinary Medicine (V.S., H.M.), and Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Institute for Stroke and Dementia Research (R.M., M.D.), Klinikum der Universität München, Munich, Germany; Center for Human Genetic Research (C.D.A., F.R., J.R.) and J. Philip Kistler Stroke Research Center (C.D.A., F.R., N.S.R., J.R.) and Division of Neurocritical Care and Emergency Neurology (C.D.A., F.R., J.R.), Department of Neurology, Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (C.D.A., F.R., J.R.), Broad Institute, Cambridge, MA; Population Health Research Institute (M.C., M.O., G.P.), McMaster University, Hamilton Health Sciences Centre, Ontario, Canada; Department of Medicine (T.D., B.D.M.), University of Maryland School of Medicine, Baltimore; Division of Neurocritical Care and Emergency Neurology (G.J.F.), Department of Neurology, Yale University School of Medicine, New Haven, CT; Stroke Pharmacogenomics and Genetics (I.F.-C.), Fundació Docència i Recerca Mutua Terrassa, Mutua de Terrassa Hospital; Neurovascular Research Unit (J.J.-C.), Department of Neurology, and Program in Inflammation and Cardiovascular Disorders (J.J.-C.), Institut Municipal d'Investigacio´Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Spain; Department of Clinical Sciences Lund (A.L.), Neurology, Lund University; Department of Neurology and Rehabilitation Medicine (A.L., M.S.), Neurology, Skåne University Hospital, Lund, Sweden; Neurovascular Research Laboratory and Neurovascular Unit (J.M.), Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Spain; HRB Clinical Research Facility (M.O.), NUI Galway, and University Hospital Galway, Ireland; Department of Neurology (A.S.), Jagiellonian University Medical College, Krakow, Poland; Cardiovascular Epidemiology Research Group (M.S.), Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Clinical Neurosciences (M.T., H.S.M.), University of Cambridge, UK; Department of Neurology (S.L.P.), Brain Centre Rudolf Magnus, University Medical Center Utrecht, the Netherlands; Boston University Schools of Medicine and Public Health (S.S.); Framingham Heart Study (S.S.), Framingham, MA; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia, Charlottesville; Department of Neurology (D.W.), University of Cincinnati College of Medicine, OH; Geriatrics Research and Education Clinical Center (B.D.M.), Baltimore Veterans Administration Medical Center, MD; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.

Abstract

OBJECTIVE:

To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.

METHODS:

We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.

RESULTS:

A locus in COL4A2 was associated (significance threshold p < 3.5 × 10-4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11-1.24, p = 6.62 × 10-8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13-1.44, p = 5.76 × 10-5). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10-4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10-1.37, p = 1.90 × 10-4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.

CONCLUSIONS:

These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.

PMID:
28954878
PMCID:
PMC5664302
DOI:
10.1212/WNL.0000000000004560
[Indexed for MEDLINE]
Free PMC Article

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