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Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.

Benjamin F J Verhaaren 1 Stéphanie Debette 2 Joshua C Bis 3 Jennifer A Smith 4 M Kamran Ikram 1, 5 Hieab H Adams 6 Ashley H Beecham 7 Kumar B Rajan 8 Lorna M Lopez 9 Sandra Barral 9 Mark A van Buchem 10 Jeroen van der Grond 11 Albert V Smith 12, 13 Katrin Hegenscheid 14 Neelum T Aggarwal 8 Mariza de Andrade 15 Elizabeth J Atkinson 16 Marian Beekman 17 Alexa S Beiser 18, 19 Susan H Blanton 20 Eric Boerwinkle 21 Adam M Brickman 22 R Nick Bryan 23 Ganesh Chauhan 24 Christopher P L H Chen 25 Vincent Chouraki 26 Anton J M de Craen 27 Fabrice Crivello 28 Ian J Deary 29 Joris Deelen 30 Philip L de Jager 31, 32, 33 Carole Dufouil 2 Mitchell S V Elkind 34 Denis A Evans 35 Paul Freudenberger 36 Rebecca F Gottesman 37 Vilmundur Guðnason 38, 39 Mohamad Habes 23, 40 Susan R Heckbert 41, 42 Gerardo Heiss 43 Saima Hilal 44 Edith Hofer 45, 46 Albert Hofman 1, 5 Carla A Ibrahim-Verbaas 1 David S Knopman 47 Cora E Lewis 48 Jiemin Liao 49 David C M Liewald 9 Michelle Luciano 50 Aad van der Lugt 1 Oliver O Martinez 51 Richard Mayeux 52 Bernard Mazoyer 28 Mike Nalls 53 Matthias Nauck 54 Wiro J Niessen 1, 55 Ben A Oostra 1 Bruce M Psaty 56, 57, 41, 42, 58 Kenneth M Rice 59 Jerome I Rotter 60 Bettina von Sarnowski 61 Helena Schmidt 62 Pamela J Schreiner 63 Maaike Schuur 1 Stephen S Sidney 64 Sigurdur Sigurdsson 65, 66 P Eline Slagboom 30 David J M Stott 67 John C van Swieten 1 Alexander Teumer 68 Anna Maria Töglhofer 69 Matthew Traylor 70 Stella Trompet 71 Stephen T Turner 72 Christophe Tzourio 2 Hae-Won Uh 73 André G Uitterlinden 1, 5 Meike W Vernooij 1 Jing J Wang 74, 19 Tien Y Wong 75, 76 Joanna M Wardlaw 9 B Gwen Windham 77 Katharina Wittfeld 14, 78 Christiane Wolf 79, 80 Clinton B Wright 81 Qiong Yang 82 Wei Zhao 83 Alex Zijdenbos 84 J Wouter Jukema 71 Ralph L Sacco 85, 86 Sharon L R Kardia 4 Philippe Amouyel 87 Thomas H Mosley 88 W T Longstreth 3 Charles C Decarli 89 Cornelia M van Duijn 1, 5, 90 Reinhold Schmidt 91 Lenore J Launer 92 Hans J Grabe 93 Sudha S Seshadri 18 M Arfan Ikram 1, 5 Myriam Fornage 21, 94
Abstract : 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. 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). 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.
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Submitted on : Monday, September 14, 2015 - 11:52:01 AM
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Benjamin F J Verhaaren, Stéphanie Debette, Joshua C Bis, Jennifer A Smith, M Kamran Ikram, et al.. Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.. Circulation: Cardiovascular Genetics, American Heart Association, 2015, 8 (2), pp.398-409. ⟨10.1161/CIRCGENETICS.114.000858⟩. ⟨hal-01198723⟩



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