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Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.
Friday,2015-04-17 14:06 America/Los_Angeles — zdrager
| Title | Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. |
| Publication Type | Journal Article |
| Year of Publication | 2015 |
| Authors | Verhaaren, BFJ, Debette, S, Bis, JC, Smith, JA, M Ikram, K, Adams, HH, Beecham, AH, Rajan, KB, Lopez, LM, Barral, S, van Buchem, MA, van der Grond, J, Smith, AV, Hegenscheid, K, Aggarwal, NT, de Andrade, M, Atkinson, EJ, Beekman, M, Beiser, AS, Blanton, SH, Boerwinkle, E, Brickman, AM, R Bryan, N, Chauhan, G, Chen, CPLH, Chouraki, V, de Craen, AJM, Crivello, F, Deary, IJ, Deelen, J, De Jager, PL, Dufouil, C, Elkind, MSV, Evans, DA, Freudenberger, P, Gottesman, RF, Guðnason, V, Habes, M, Heckbert, SR, Heiss, G, Hilal, S, Hofer, E, Hofman, A, Ibrahim-Verbaas, CA, Knopman, DS, Lewis, CE, Liao, J, Liewald, DCM, Luciano, M, van der Lugt, A, Martinez, OO, Mayeux, R, Mazoyer, B, Nalls, M, Nauck, M, Niessen, WJ, Oostra, BA, Psaty, BM, Rice, KM, Rotter, JI, von Sarnowski, B, Schmidt, H, Schreiner, PJ, Schuur, M, Sidney, SS, Sigurdsson, S, P Slagboom, E, Stott, DJM, van Swieten, JC, Teumer, A, Töglhofer, AMaria, Traylor, M, Trompet, S, Turner, ST, Tzourio, C, Uh, H-W, Uitterlinden, AG, Vernooij, MW, Wang, JJ, Wong, TY, Wardlaw, JM, B Windham, G, Wittfeld, K, Wolf, C, Wright, CB, Yang, Q, Zhao, W, Zijdenbos, A, J Jukema, W, Sacco, RL, Kardia, SLR, Amouyel, P, Mosley, TH, Longstreth, WT, DeCarli, CC, van Duijn, CM, Schmidt, R, Launer, LJ, Grabe, HJ, Seshadri, SS, Ikram, AM, Fornage, M |
| Journal | Circ Cardiovasc Genet |
| Volume | 8 |
| Issue | 2 |
| Pagination | 398-409 |
| Date Published | 2015 Apr |
| ISSN | 1942-3268 |
| Keywords | Aged, Aged, 80 and over, Chromosomes, Human, Continental Population Groups, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Models, Genetic, Stroke, White Matter |
| Abstract | <p><b>BACKGROUND: </b>The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.</p><p><b>METHODS AND RESULTS: </b>We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).</p><p><b>CONCLUSIONS: </b>We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.</p> |
| DOI | 10.1161/CIRCGENETICS.114.000858 |
| Alternate Journal | Circ Cardiovasc Genet |
| PubMed ID | 25663218 |
| PubMed Central ID | PMC4427240 |
| Grant List | AG023629 / AG / NIA NIH HHS / United States AG15928 / AG / NIA NIH HHS / United States BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom G0700704 / / Medical Research Council / United Kingdom G0701120 / / Medical Research Council / United Kingdom G1001401 / / Medical Research Council / United Kingdom HL080295 / HL / NHLBI NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States HL103612 / HL / NHLBI NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States HL120393 / HL / NHLBI NIH HHS / United States MR/K026992/1 / / Medical Research Council / United Kingdom N01HC15103 / HC / NHLBI NIH HHS / United States N01HC55222 / HC / NHLBI NIH HHS / United States N01HC85079 / HC / NHLBI NIH HHS / United States N01HC85080 / HC / NHLBI NIH HHS / United States N01HC85081 / HC / NHLBI NIH HHS / United States N01HC85082 / HC / NHLBI NIH HHS / United States N01HC85083 / HC / NHLBI NIH HHS / United States N01HC85086 / HC / NHLBI NIH HHS / United States P30 AG010129 / AG / NIA NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States R01 AG008122 / AG / NIA NIH HHS / United States R01 AG011101 / AG / NIA NIH HHS / United States R01 AG030146 / AG / NIA NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States R01 HL084099 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States R01 NS087541 / NS / NINDS NIH HHS / United States R01HL086694 / HL / NHLBI NIH HHS / United States R01HL087641 / HL / NHLBI NIH HHS / United States R01HL59367 / HL / NHLBI NIH HHS / United States R01HL70825 / HL / NHLBI NIH HHS / United States U01 AG049505 / AG / NIA NIH HHS / United States U01HG004402 / HG / NHGRI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States UL1RR025005 / RR / NCRR NIH HHS / United States |