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. Vicente AM - Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis. 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. This work was funded in part by NIH grants U01 NS069208 and P30 DK072488 (SiGN). M.D. and R.M. were supported by grants from the Deutsche Forschungsgemeinschaft (CRC 1123 [B3] and Munich Cluster for Systems Neurology [SyNergy]), the German Federal Ministry of Education and Research (BMBF, e:Med programme e:AtheroSysMed), the FP7/2007–2103 European Union project CVgenes@target (grant agreement Health-F2-2013-601456), the European Union Horizon 2020 projects SVDs@target (grant agreement 66688) and CoSTREAM (grant agreement 667375), the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain), the Vascular Dementia Research Foundation, and the Jackstaedt Foundation. G.P. and M.C. were supported by the Canadian Stroke Network, Canadian Institutes of Health Research, and Heart & Stroke Foundation. N.S.R. acknowledges the National Institute of Neurologic Disorders and Stroke K23NS064052, R01NS086905, and R01NS082285. info:eu-repo/semantics/publishedVersion