Abstract

Alzheimer’s disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. We show that self-report of parental history of Alzheimer’s dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data (n = 74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci (P < 5 × 10−8) are identified. These contain genes relevant for AD and neurodegeneration: ADAM10, BCKDK/KAT8 and ACE. Novel gene-based loci include drug targets such as VKORC1 (warfarin dose). We report evidence that the association of SNPs in the TOMM40 gene with AD is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. However, it is likely that multiple variants are affecting the trait and gene methylation/expression. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, as they contain genes that are drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications.

Details

Title
GWAS on family history of Alzheimer’s disease
Author
Marioni, Riccardo E 1 ; Harris, Sarah E 1 ; Zhang, Qian 2 ; McRae, Allan F 2   VIAFID ORCID Logo  ; Hagenaars, Saskia P 3 ; Hill, W David 4 ; Davies, Gail 5 ; Ritchie, Craig W 6 ; Gale, Catharine R 7 ; Starr, John M 8 ; Goate, Alison M 9   VIAFID ORCID Logo  ; Porteous, David J 1   VIAFID ORCID Logo  ; Yang, Jian 10   VIAFID ORCID Logo  ; Evans, Kathryn L 11 ; Deary, Ian J 4 ; Wray, Naomi R 10   VIAFID ORCID Logo  ; Visscher, Peter M 12   VIAFID ORCID Logo 

1  Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK 
2  Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia 
3  Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK 
4  Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Department of Psychology, University of Edinburgh, Edinburgh, UK 
5  Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK 
6  Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK 
7  Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Department of Psychology, University of Edinburgh, Edinburgh, UK; MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK 
8  Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK 
9  Departments of Neuroscience, Neurology and Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA 
10  Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia 
11  Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK 
12  Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia 
Pages
1-7
Publication year
2018
Publication date
May 2018
Publisher
Nature Publishing Group
e-ISSN
21583188
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41398-018-0150-6
ProQuest document ID
2041130512
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.