Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI
Authors: Verhaaren Benjamin F.J. , Debette Stéphanie , Bis Joshua C. , Smith Jennifer A. , Ikram M. Kamran , Adams Hieab H. , Beecham Ashley H. , Rajan Kumar B. , Lopez Lorna M. , Barral Sandra , van Buchem Mark A. , van der Grond Jeroen , Smith Albert V. , Hegenscheid Katrin , Aggarwal Neelum T. , de Andrade Mariza , Atkinson Elizabeth J. , Beekman Marian , Beiser Alexa S. , Blanton Susan H. , Boerwinkle Eric , Brickman Adam M. , Bryan R. Nick , Chauhan Ganesh , Chen Christopher P.L.H. , Chouraki Vincent , de Craen Anton J.M. , Crivello Fabrice , Deary Ian J. , Deelen Joris , De Jager Philip L. , Dufouil Carole , Elkind Mitchell S.V. , Evans Denis A. , Freudenberger Paul , Gottesman Rebecca F. , Guðnason Vilmundur , Habes Mohamad , Heckbert Susan R. , Heiss Gerardo , Hilal Saima , Hofer Edith , Hofman Albert , Ibrahim-Verbaas Carla A. , Knopman David S. , Lewis Cora E. , Liao Jiemin , Liewald David C.M. , Luciano Michelle , van der Lugt Aad , Martinez Oliver O. , Mayeux Richard , Mazoyer Bernard , Nalls Mike , Nauck Matthias , Niessen Wiro J. , Oostra Ben A. , Psaty Bruce M. , Rice Kenneth M. , Rotter Jerome I. , von Sarnowski Bettina , Schmidt Helena , Schreiner Pamela J. , Schuur Maaike , Sidney Stephen S. , Sigurdsson Sigurdur , Slagboom P. Eline , Stott David J.M. , van Swieten John C. , Teumer Alexander , Töglhofer Anna Maria , Traylor Matthew , Trompet Stella , Turner Stephen T. , Tzourio Christophe , Uh Hae-Won , Uitterlinden André G. , Vernooij Meike W. , Wang Jing J. , Wong Tien Y. , Wardlaw Joanna M. , Windham B. Gwen , Wittfeld Katharina , Wolf Christiane , Wright Clinton B. , Yang Qiong , Zhao Wei , Zijdenbos Alex , Jukema J. Wouter , Sacco Ralph L. , Kardia Sharon L.R. , Amouyel Philippe , Mosley Thomas H. , Longstreth W. T. , DeCarli Charles C. , van Duijn Cornelia M. , Schmidt Reinhold , Launer Lenore J. , Grabe Hans J. , Seshadri Sudha S. , Ikram M. Arfan , Fornage Myriam 
Published: February 2015

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.