TY - JOUR
T1 - Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI
AU - Verhaaren, Benjamin F.J.
AU - Debette, Stéphanie
AU - Bis, Joshua C.
AU - Smith, Jennifer A.
AU - Ikram, M. Kamran
AU - Adams, Hieab H.
AU - Beecham, Ashley H.
AU - Rajan, Kumar B.
AU - Lopez, Lorna M.
AU - Barral, Sandra
AU - Van Buchem, Mark A.
AU - Van Der Grond, Jeroen
AU - Smith, Albert V.
AU - Hegenscheid, Katrin
AU - Aggarwal, Neelum T.
AU - De Andrade, Mariza
AU - Atkinson, Elizabeth J.
AU - Beekman, Marian
AU - Beiser, Alexa S.
AU - Blanton, Susan H.
AU - Boerwinkle, Eric
AU - Brickman, Adam M.
AU - Bryan, R. Nick
AU - Chauhan, Ganesh
AU - Chen, Christopher P.L.H.
AU - Chouraki, Vincent
AU - De Craen, Anton J.M.
AU - Crivello, Fabrice
AU - Deary, Ian J.
AU - Deelen, Joris
AU - De Jager, Philip L.
AU - Dufouil, Carole
AU - Elkind, Mitchell S.V.
AU - Evans, Denis A.
AU - Freudenberger, Paul
AU - Gottesman, Rebecca F.
AU - Gunason, Vilmundur
AU - Habes, Mohamad
AU - Heckbert, Susan R.
AU - Heiss, Gerardo
AU - Hilal, Saima
AU - Hofer, Edith
AU - Hofman, Albert
AU - Ibrahim-Verbaas, Carla A.
AU - Knopman, David S.
AU - Lewis, Cora E.
AU - Liao, Jiemin
AU - Liewald, David C.M.
AU - Luciano, Michelle
AU - Van Der Lugt, Aad
AU - Martinez, Oliver O.
AU - Mayeux, Richard
AU - Mazoyer, Bernard
AU - Nalls, Mike
AU - Nauck, Matthias
AU - Niessen, Wiro J.
AU - Oostra, Ben A.
AU - Psaty, Bruce M.
AU - Rice, Kenneth M.
AU - Rotter, Jerome I.
AU - Von Sarnowski, Bettina
AU - Schmidt, Helena
AU - Schreiner, Pamela J.
AU - Schuur, Maaike
AU - Sidney, Stephen S.
AU - Sigurdsson, Sigurdur
AU - Slagboom, P. Eline
AU - Stott, David J.M.
AU - Van Swieten, John C.
AU - Teumer, Alexander
AU - Töglhofer, Anna Maria
AU - Traylor, Matthew
AU - Trompet, Stella
AU - Turner, Stephen T.
AU - Tzourio, Christophe
AU - Uh, Hae Won
AU - Uitterlinden, André G.
AU - Vernooij, Meike W.
AU - Wang, Jing J.
AU - Wong, Tien Y.
AU - Wardlaw, Joanna M.
AU - Windham, B. Gwen
AU - Wittfeld, Katharina
AU - Wolf, Christiane
AU - Wright, Clinton B.
AU - Yang, Qiong
AU - Zhao, Wei
AU - Zijdenbos, Alex
AU - Jukema, J. Wouter
AU - Sacco, Ralph L.
AU - Kardia, Sharon L.R.
AU - Amouyel, Philippe
AU - Mosley, Thomas H.
AU - Longstreth, W. T.
AU - DeCarli, Charles C.
AU - Van Duijn, Cornelia M.
AU - Schmidt, Reinhold
AU - Launer, Lenore J.
AU - Grabe, Hans J.
AU - Seshadri, Sudha S.
AU - Ikram, M. Arfan
AU - Fornage, Myriam
AU - Neurology Working Group of the CHARGE Consortium
PY - 2015/4/4
Y1 - 2015/4/4
N2 - Background-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. Methods and Results-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). Conclusions-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.
AB - Background-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. Methods and Results-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). Conclusions-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.
KW - cerebral small vessel diseases
KW - cerebrovascular disorders
KW - genome-wide association study
KW - hypertension
KW - leukoencephalopathies
KW - polymorphisms, single nucleotide
UR - http://www.scopus.com/inward/record.url?scp=84942844748&partnerID=8YFLogxK
U2 - 10.1161/CIRCGENETICS.114.000858
DO - 10.1161/CIRCGENETICS.114.000858
M3 - Article
C2 - 25663218
AN - SCOPUS:84942844748
VL - 8
SP - 398
EP - 409
JO - Circulation-cardiovascular genetics
JF - Circulation-cardiovascular genetics
SN - 1942-325X
IS - 2
ER -