PuSH - Publication Server of Helmholtz Zentrum München: Genome-wide association analysis of young onset stroke identifies a locus on chromosome 10q25 near <em>HABP2</em>.

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Cheng, Y.C.* ; Stanne, T.M.* ; Giese, A.K.* ; Ho, W.K.* ; Traylor, M.* ; Amouyel, P.* ; Holliday, E.G.* ; Malik, R.* ; Xu, H.* ; Kittner, S.J.* ; Cole, J.W.* ; O'Connell, J.R.* ; Danesh, J.* ; Rasheed, A.* ; Zhao, W.* ; Engelter, S.T.* ; Grond-Ginsbach, C.* ; Kamatani, Y.* ; Lathrop, M* ; Leys, D.* ; Thijs, V.* ; Metso, T.M.* ; Tatlisumak, T.* ; Pezzini, A.* ; Parati, E.A.* ; Norrving, B.* ; Bevan, S.* ; Rothwell, P.M.* ; Sudlow, C.* ; Slowik, A.* ; Lindgren, A.* ; Walters, M.R.* ; Jannes, J.* ; Shen, J.* ; Crosslin, D.R.* ; Doheny, K.F.* ; Laurie, C.C.* ; Kanse, S.M.* ; Bis, J.C.* ; Fornage, M.* ; Mosley, T.H.* ; Hopewell, J.C.* ; Strauch, K. ; Müller-Nurasyid, M. ; Gieger, C. ; Waldenberger, M. ; Peters, A. ; Meisinger, C. ; Ikram, M.A.* ; Longstreth, W.T. Jr.* ; Meschia, J.F.* ; Seshadri, S* ; Sharma, P.* ; Worrall, B.B.* ; Jern, C.* ; Levi, C.* ; Dichgans, M.* ; Boncoraglio, G.B.* ; Markus, H.S.* ; Debette, S.* ; Rolfs, A.* ; Saleheen, D.* ; Mitchell, B.D.*

Genome-wide association analysis of young onset stroke identifies a locus on chromosome 10q25 near HABP2.

Stroke 47, 307-316 (2016)

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BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years. METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

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