Verhaaren, Benjamin F.J. and Debette, Stéphanie and Bis, Joshua C. and Smith, Jennifer A. and Ikram, M. Kamran and Adams, Hieab H. and Beecham, Ashley H. and Rajan, Kumar B. and Lopez, Lorna M. and Barral, Sandra and van Buchem, Mark A. and van der Grond, Jeroen and Smith, Albert V. and Hegenscheid, Katrin and Aggarwal, Neelum T. and de Andrade, Mariza and Atkinson, Elizabeth J. and Beekman, Marian and Beiser, Alexa S. and Blanton, Susan H. and Boerwinkle, Eric and Brickman, Adam M. and Bryan, R. Nick and Chauhan, Ganesh and Chen, Christopher P.L.H. and Chouraki, Vincent and de Craen, Anton J.M. and Crivello, Fabrice and Deary, Ian J. and Deelen, Joris and De Jager, Philip L. and Dufouil, Carole and Elkind, Mitchell S.V. and Evans, Denis A. and Freudenberger, Paul and Gottesman, Rebecca F. and Guðnason, Vilmundur and Habes, Mohamad and Heckbert, Susan R. and Heiss, Gerardo and Hilal, Saima and Hofer, Edith and Hofman, Albert and Ibrahim-Verbaas, Carla A. and Knopman, David S. and Lewis, Cora E. and Liao, Jiemin and Liewald, David C.M. and Luciano, Michelle and van der Lugt, Aad and Martinez, Oliver O. and Mayeux, Richard and Mazoyer, Bernard and Nalls, Mike and Nauck, Matthias and Niessen, Wiro J. and Oostra, Ben A. and Psaty, Bruce M. and Rice, Kenneth M. and Rotter, Jerome I. and von Sarnowski, Bettina and Schmidt, Helena and Schreiner, Pamela J. and Schuur, Maaike and Sidney, Stephen S. and Sigurdsson, Sigurdur and Slagboom, P. Eline and Stott, David J.M. and van Swieten, John C. and Teumer, Alexander and Töglhofer, Anna Maria and Traylor, Matthew and Trompet, Stella and Turner, Stephen T. and Tzourio, Christophe and Uh, Hae-Won and Uitterlinden, André G. and Vernooij, Meike W. and Wang, Jing J. and Wong, Tien Y. and Wardlaw, Joanna M. and Windham, B. Gwen and Wittfeld, Katharina and Wolf, Christiane and Wright, Clinton B. and Yang, Qiong and Zhao, Wei and Zijdenbos, Alex and Jukema, J. Wouter and Sacco, Ralph L. and Kardia, Sharon L.R. and Amouyel, Philippe and Mosley, Thomas H. and Longstreth, W. T. and DeCarli, Charles C. and van Duijn, Cornelia M. and Schmidt, Reinhold and Launer, Lenore J. and Grabe, Hans J. and Seshadri, Sudha S. and Ikram, M. Arfan and Fornage, Myriam (2015) Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI. Circulation: Cardiovascular Genetics, 8 (2). pp. 398-409. ISSN 1942-325X

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Abstract

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.

Item Type:	Article
Keywords:	cerebral small vessel diseases; cerebrovascular disorders; genome-wide association study; hypertension; leukoencephalopathies; polymorphisms, single nucleotide;
Academic Unit:	Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17223
Identification Number:	https://doi.org/10.1161/CIRCGENETICS.114.000858
Depositing User:	Lorna Lopez
Date Deposited:	24 May 2023 10:54
Journal or Publication Title:	Circulation: Cardiovascular Genetics
Publisher:	Lippincott Williams & Wilkins for the American Heart Association
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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