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, 22 Adam M Brickman 23 R Nick Bryan 24 Ganesh Chauhan 25 Christopher P L H Chen 26 Vincent Chouraki 27 Anton J M De Craen 28 Fabrice Crivello 29 Ian J Deary 30 Joris Deelen 31 Philip L De Jager 32, 33, 34 Carole Dufouil 2 Mitchell S V Elkind 35 Denis A Evans 36 Paul Freudenberger 37 Rebecca F Gottesman 38 Vilmundur Guðnason 39, 40 Mohamad Habes 24, 41 Susan R Heckbert 42, 43 Gerardo Heiss 44 Saima Hilal 45 Edith Hofer 46, 47 Albert Hofman 1, 5 Carla A Ibrahim-Verbaas 1 David S Knopman 48 Cora E Lewis 49 Jiemin Liao 50 David C M Liewald 9 Michelle Luciano 51 Aad Van Der Lugt 1 Oliver O Martinez 52 Richard Mayeux 53 Bernard Mazoyer 29 Mike Nalls 54 Matthias Nauck 55 Wiro J Niessen 1, 56 Ben A Oostra 1 Bruce M Psaty 57, 58, 42, 43, 59 Kenneth M Rice 60 Jerome I Rotter 61 Bettina Von Sarnowski 62 Helena Schmidt 63 Pamela J Schreiner 64 Maaike Schuur 1 Stephen S Sidney 65 Sigurdur Sigurdsson 66, 67 P Eline Slagboom 31 David J M Stott 68 John C Van Swieten 1 Alexander Teumer 69 Anna Maria Töglhofer 70 Matthew Traylor 71 Stella Trompet 72 Stephen T Turner 73 Christophe Tzourio 2 Hae-Won Uh 74 André G Uitterlinden 1, 5 Meike W Vernooij 1 Jing J Wang 75, 76 Tien Y Wong 77, 78 Joanna M Wardlaw 9 B Gwen Windham 79 Katharina Wittfeld 14, 80 Christiane Wolf 81, 82 Clinton B Wright 83 Qiong Yang 84 Wei Zhao 85 Alex Zijdenbos 86 J Wouter Jukema 72 Ralph L Sacco 87, 88 Sharon L R Kardia 4 Philippe Amouyel 89 Thomas H Mosley 90 W T Longstreth 3 Charles C Decarli 91 Cornelia M Van Duijn 1, 5, 92 Reinhold Schmidt 93 Lenore J Launer 94 Hans J Grabe 95 Sudha S Seshadri 18 M Arfan Ikram 1, 5 Myriam Fornage 96, 97
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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Circulation: Cardiovascular Genetics, American Heart Association, 2015, 8 (2), pp.398-409. 〈10.1161/CIRCGENETICS.114.000858〉
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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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