TY - JOUR
T1 - Genome-wide association analysis of young-onset stroke identifies a locus on chromosome 10q25 Near HABP2
AU - Cheng, Yu-Ching
AU - Stanne, Tara M.
AU - Giese, Anne-Katrin
AU - Ho, Weang Kee
AU - Traylor, Matthew
AU - Amouyel, Philippe
AU - Holliday, Elizabeth G.
AU - Malik, Rainer
AU - Xu, Huichun
AU - Kittner, Steven J.
AU - Cole, John W.
AU - O’Connell, Jeffrey R.
AU - Danesh, John
AU - Rasheed, Asif
AU - Zhao, Wei
AU - Engelter, Stefan
AU - Grond-Ginsbach, Caspar
AU - Kamatani, Yoichiro
AU - Lathrop, Mark
AU - Leys, Didier
AU - Thijs, Vincent
AU - Metso, Tina M.
AU - Tatlisumak, Turgut
AU - Pezzini, Alessandro
AU - Parati, Eugenio A.
AU - Norrving, Bo
AU - Bevan, Steve
AU - Rothwell, Peter M.
AU - Sudlow, Cathie
AU - Slowik, Agnieszka
AU - Lindgren, Arne
AU - Walters, Matthew R.
AU - WTCCC-2 Consortium, null
AU - Levi, Christopher
PY - 2016
Y1 - 2016
N2 - 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<5Ã10−6 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=9.5Ã10−9). 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.
AB - 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<5Ã10−6 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=9.5Ã10−9). 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.
UR - https://hdl.handle.net/1959.7/uws:67648
U2 - 10.1161/STROKEAHA.115.011328
DO - 10.1161/STROKEAHA.115.011328
M3 - Article
SN - 1524-4628
SN - 0039-2499
VL - 47
SP - 307
EP - 316
JO - Stroke
JF - Stroke
IS - 2
ER -