Multi-Ethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 multi-ethnic 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=1,943), 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 SNP 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 multi-ethnic meta-analysis, we identified two 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's disease (chr2p21, chr10q24), intracerebral hemorrhage (chr1q22), neuro-inflammatory diseases (chr2p21), and glioma (chr10q24, chr2p16).

CONCLUSIONS: -We identified four novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of white matter hyperintensities in addition to previously-proposed ischemic mechanisms.

Original languageEnglish
Pages (from-to)398-+
Number of pages54
JournalCirculation: Cardiovascular Genetics
Issue number2
Early online date7 Feb 2015
Publication statusPublished - Apr 2015

Keywords / Materials (for Non-textual outputs)

  • cerebral small vessel diseases
  • cerebrovascular disorders
  • genome-wide association study
  • hypertension
  • leukoencephalopathies
  • polymorphisms, single nucleotide


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