Association of Alzheimer's disease GWAS loci with MRI markers of brain aging

Ganesh Chauhan (1) , Hieab H.H. Adams (2) , Joshua C. Bis (3) , Galit Weinstein (4) , Lei Yu (5) , Anna Maria Töglhofer (6) , Albert Vernon Smith (7, 8) , Sven J. van Der Lee (9) , Rebecca F. Gottesman (10) , Russell Thomson (11) , Jing Wang , Qiong Yang (12) , Wiro J. Niessen (13, 9) , Oscar L. Lopez (14) , James T. Becker (15) , Thanh G. Phan (16) , Richard J. Beare (17, 18) , Konstantinos Arfanakis (19, 20) , Debra Fleischman (20, 21) , Meike W. Vernooij (9) , Bernard Mazoyer (22) , Helena Schmidt (23) , Velandai Srikanth (11, 18) , David S. Knopman (24) , Clifford R. Jack (21) , Philippe Amouyel (25) , Albert Hofman (26, 9) , Charles Decarli (27) , Christophe Tzourio (1) , Cornelia M. van Duijn (9, 26, 28) , David A. Bennett (20) , Reinhold Schmidt (29) , William T. Longstreth (3) , Thomas H. Mosley (30) , Myriam Fornage (31, 32) , Lenore J. Launer (33) , Sudha Seshadri (4) , M. Arfan Ikram (9, 26) , Stephanie Debette (34)

1 INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France
2 Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique
3 University of Washington [Seattle]
4 BUSM - Boston University School of Medicine
5 HDU - Hangzhou Dianzi University
6 Medical University of Graz
7 ITU - JRC Institute for Transuranium Elements [Karlsruhe]
8 DMSM - Department of Materials Science and Metallurgy [Cambridge University]
9 Erasmus MC - Erasmus University Medical Center [Rotterdam]
10 Johns Hopkins University School of Medicine [Baltimore]
11 Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia
12 University of Miami [Coral Gables]
13 TU Delft - Delft University of Technology
14 Estación Experimental de Pastos y Forrajes ‘Indio Hatuey’
15 KIT - Karlsruhe Institute of Technology
16 Institut de Mathématiques [Hanoi]
17 MCRI - Murdoch Children's Research Institute
18 Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University
19 Department of Biomedical Engineering
20 Rush University Medical Center [Chicago]
21 Department of Radiology
22 GIN - UMR 5296 - Groupe d'Imagerie Neurofonctionnelle
23 Department of Physics [Stockholm]
24 Mayo Clinic [Rochester]
25 Institut Pasteur de Lille
26 Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands
27 Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento
28 Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands
29 AIT - Austrian Institute of Technology [Vienna]
30 UMMC - University of Mississippi Medical Center
31 Human Genetics Center
32 UTHealth - The University of Texas Health Science Center at Houston
33 Donders Institute for Brain, Cognition and Behaviour
34 Epidémiologie et Biostatistique [Bordeaux]

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

Domaines: Sciences cognitives; Neurosciences

Ganesh Chauhan, Hieab H.H. Adams, Joshua C. Bis, Galit Weinstein, Lei Yu, et al.. Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. Neurobiology of Aging, 2015, 36 (4), pp.1765.e7-16. ⟨10.1016/j.neurobiolaging.2014.12.028⟩. ⟨hal-01196175⟩