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

Ganesh Chauhan; Hieab H H Adams; Joshua C Bis; Galit Weinstein; Lei Yu; Anna Maria Töglhofer; Albert Vernon Smith; Sven J van der Lee; Rebecca F Gottesman; Russell Thomson; Jing Wang; Qiong Yang; Wiro J Niessen; Oscar L Lopez; James T Becker; Thanh G Phan; Richard J Beare; Konstantinos Arfanakis; Debra Fleischman; Meike W Vernooij; Bernard Mazoyer; Helena Schmidt; Velandai Srikanth; David S Knopman; Clifford R Jack Jr; Philippe Amouyel; Albert Hofman; Charles DeCarli; Christophe Tzourio; Cornelia M van Duijn; David A Bennett; Reinhold Schmidt; William T Longstreth Jr; Thomas H Mosley; Myriam Fornage; Lenore J Launer; Sudha Seshadri; M Arfan Ikram; Stephanie Debette

doi:10.1016/j.neurobiolaging.2014.12.028

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

Neurobiol Aging. 2015 Apr;36(4):1765.e7-1765.e16. doi: 10.1016/j.neurobiolaging.2014.12.028. Epub 2015 Jan 6.

Authors

Ganesh Chauhan¹, Hieab H H Adams², Joshua C Bis³, Galit Weinstein⁴, Lei Yu⁵, Anna Maria Töglhofer⁶, Albert Vernon Smith⁷, Sven J van der Lee⁸, Rebecca F Gottesman⁹, Russell Thomson¹⁰, Jing Wang¹¹, Qiong Yang¹¹, Wiro J Niessen¹², Oscar L Lopez¹³, James T Becker¹⁴, Thanh G Phan¹⁵, Richard J Beare¹⁶, Konstantinos Arfanakis¹⁷, Debra Fleischman¹⁸, Meike W Vernooij², Bernard Mazoyer¹⁹, Helena Schmidt⁶, Velandai Srikanth²⁰, David S Knopman²¹, Clifford R Jack Jr²², Philippe Amouyel²³, Albert Hofman⁸, Charles DeCarli²⁴, Christophe Tzourio²⁵, Cornelia M van Duijn²⁶, David A Bennett⁵, Reinhold Schmidt²⁷, William T Longstreth Jr²⁸, Thomas H Mosley²⁹, Myriam Fornage³⁰, Lenore J Launer³¹, Sudha Seshadri⁴, M Arfan Ikram³², Stephanie Debette³³

Affiliations

¹ INSERM U897, University of Bordeaux, Bordeaux, France; University of Bordeaux, Bordeaux, FranceINSERM U897, University of Bordeaux, Bordeaux, France.
² Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands.
³ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁴ Department of Neurology, Boston University School of Medicine, Boston, MA, USA; The Framingham Heart Study, Boston, MA, USA.
⁵ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
⁶ Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria.
⁷ Icelandic Heart Association, Iceland; Department of Medicine, University of Iceland, Reykjavik, Iceland.
⁸ Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
⁹ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, USA; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.
¹⁰ Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
¹¹ The Framingham Heart Study, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹² Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands.
¹³ Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁴ Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Psychology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁵ Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Melbourne, Victoria, Australia.
¹⁶ Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Melbourne, Victoria, Australia; Developmental Imaging Group, Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
¹⁷ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA.
¹⁸ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
¹⁹ Groupe d'Imagerie Neurofonctionnelle, UMR5296, CNRS, CEA, Université de Bordeaux, Bordeaux, France.
²⁰ Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Melbourne, Victoria, Australia; Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
²¹ Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA.
²² Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, USA.
²³ Department of Epidemiology and Public Health, Pasteur Institute of Lille, Lille, France; INSERM, U744, Lille, France; Université Lille 2, Lille, France.
²⁴ Department of Neurology, University of California at Davis, Davis, CA, USA.
²⁵ INSERM U897, University of Bordeaux, Bordeaux, France.
²⁶ Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging, Leiden, the Netherlands; Center for Medical Systems Biology, Leiden, the Netherlands.
²⁷ Department of Neurology, Clinical Division of Neurogeriatrics, Medical University of Graz, Austria.
²⁸ Departments of Neurology and Epidemiology, University of Washington, Seattle, WA, USA.
²⁹ Department of Medicine-Geriatrics/Gerontology, University of Mississippi Medical Center, Jackson, MS, USA.
³⁰ The Human Genetics Center and Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, USA.
³¹ Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³² Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging, Leiden, the Netherlands.
³³ INSERM U897, University of Bordeaux, Bordeaux, France; University of Bordeaux, Bordeaux, FranceINSERM U897, University of Bordeaux, Bordeaux, France; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Bordeaux University Hospital, Bordeaux, France. Electronic address: sdebette@bu.edu.

PMID: 25670335
PMCID: PMC4391343
DOI: 10.1016/j.neurobiolaging.2014.12.028

Abstract

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.

Keywords: Alzheimer; GWAS; Genetic risk score; Hippocampal volume; MRI-Markers.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics*
Aging / pathology*
Alleles
Alzheimer Disease / genetics*
Alzheimer Disease / pathology*
Apolipoproteins E / genetics
Brain / pathology*
Female
Genome-Wide Association Study*
Hippocampus / pathology
Humans
Magnetic Resonance Imaging*
Male
Organ Size / genetics
Polymorphism, Single Nucleotide
Risk
Sialic Acid Binding Ig-like Lectin 3 / genetics

Substances

Apolipoproteins E
Sialic Acid Binding Ig-like Lectin 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding