BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0x10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14x10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91x10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA.
AD - From the Indiana University School of Medicine, Indianapolis (T.F., D.L., D.K., J.M.); University Medical Center Utrecht, Utrecht, The Netherlands (F.v.H., G.R., Y.R.); Kuopio University Hospital, Kuopio, Finland (M.I.K., M.v.u.z.F., J.E.J.); University of Eastern Finland, Kuopio, Finland (M.I.K., M.v.u.z.F., J.E.J.); Massachusetts General Hospital and Harvard Medical School, Boston (M.I.K., A.P., S.R.); Broad Institute of Harvard and MIT, Cambridge, MA (M.I.K., A.P., S.R.); University of Sydney and Royal Prince Alfred Hospital, Sydney, Australia (C.S.A.); Mayo Clinic, Rochester, MN (R.D.B., J. Huston I.M.); Columbia University School of Medicine, New York, NY (E.S.C.); University of Helsinki, Helsinki, Finland (J.G.E., E.I.G.); Folkhalsan Research Center, Helsinki, Finland (J.G.E.); National Institute for Health and Welfare, Helsinki, Finland (J.G.E.); Vasa Central Hospital, Vasa, Finland (J.G.E.); Helsinki University Central Hospital, Helsinki, Finland (J.G.E., E.I.G., A.L., J. Hernesniemi, R.K., H.L., M.N.); University of Cincinnati, OH (M. Flaherty, D.K., C.J.M., L.S., D.W., J.B.); University of Texas Health Science Center at Houston (M. Fornage); Radboud University Medical Center, Nijmegen, The Netherlands (L.A.K., S.H.V.); University of California, San Francisco (N.K.); University of Mississippi Medical Center, Jackson (T.H.M.); Jagiellonian University Medical College, Krakow, Poland (M.M., J.P., A.S.); The Wellcome Trust Sanger Institute, Cambridge, United Kingdom (A.P.); University of Montreal, Montreal, Quebec, Canada (G.R.); and University of Virginia School of Medicine, Charlottesville (B.B.W.). tforoud@iu.edu.BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0x10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14x10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91x10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA.
PY - 2014 SN - 1524-4628 (Electronic)