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

Benjamin F J Verhaaren 1, 2 Stéphanie Debette 3 Joshua C Bis 4 Jennifer A Smith 5 M Kamran Ikram 2, 6, 7 Hieab H Adams 8 Ashley H Beecham 9 Kumar B Rajan 10 Lorna M Lopez 11 Sandra Barral 12 Mark A Van Buchem 13 Jeroen Van Der Grond 14 Albert V Smith 15, 16 Katrin Hegenscheid 17 Neelum T Aggarwal 10 Mariza De Andrade 18 Elizabeth J Atkinson 19 Marian Beekman 20 Alexa S Beiser 21, 22 Susan H Blanton 23 Eric Boerwinkle 24, 25 Adam M Brickman 26 R Nick Bryan 27 Ganesh Chauhan 28 Christopher P L H Chen 29 Vincent Chouraki 30 Anton J M De Craen 31 Fabrice Crivello 32 Ian J Deary 33 Joris Deelen 34 Philip L De Jager 35, 36, 37 Carole Dufouil 3 Mitchell S V Elkind 38 Denis A Evans 39 Paul Freudenberger 40 Rebecca F Gottesman 41 Vilmundur Guðnason 42, 43 Mohamad Habes 27, 44 Susan R Heckbert 45, 46 Gerardo Heiss 47 Saima Hilal 48 Edith Hofer 49, 50 Albert Hofman 6, 7 Carla A Ibrahim-Verbaas 6, 51 David S Knopman 52 Cora E Lewis 53 Jiemin Liao 54 David C M Liewald 11 Michelle Luciano 55 Aad Van Der Lugt 56 Oliver O Martinez 57 Richard Mayeux 58 Bernard Mazoyer 32 Mike Nalls 59 Matthias Nauck 60 Wiro J Niessen 56, 2, 61 Ben A Oostra 62, 51 Bruce M Psaty 63, 64, 45, 46, 65 Kenneth M Rice 66 Jerome I Rotter 67 Bettina Von Sarnowski 68 Helena Schmidt 69 Pamela J Schreiner 70 Maaike Schuur 6, 51 Stephen S Sidney 71 Sigurdur Sigurdsson 72, 73 P Eline Slagboom 34 David J M Stott 74 John C Van Swieten 2 Alexander Teumer 75 Anna Maria Töglhofer 76 Matthew Traylor 77 Stella Trompet 78 Stephen T Turner 79 Christophe Tzourio 3 Hae-Won Uh 80 André G Uitterlinden 81, 7 Meike W Vernooij 2, 6 Jing J Wang 82, 83 Tien Y Wong 84, 85 Joanna M Wardlaw 12 B Gwen Windham 86 Katharina Wittfeld 87, 88 Christiane Wolf 89, 90 Clinton B Wright 91 Qiong Yang 92 Wei Zhao 93 Alex Zijdenbos 94 J Wouter Jukema 78 Ralph L Sacco 95, 96 Sharon L R Kardia 5 Philippe Amouyel 97 Thomas H Mosley 98, 99 W T Longstreth 100, 101 Charles C Decarli 102 Cornelia M Van Duijn 51, 7, 103 Reinhold Schmidt 104 Lenore J Launer 105 Hans J Grabe 106 Sudha S Seshadri 21 M Arfan Ikram 2, 6, 7 Myriam Fornage 107, 108
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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https://hal.archives-ouvertes.fr/hal-01198723
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Soumis le : lundi 14 septembre 2015 - 11:52:01
Dernière modification le : mardi 11 juillet 2017 - 09:49:17

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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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