GWAS on family history of Alzheimer's disease
GWAS on family history of Alzheimer's disease
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.
Marioni, Riccardo E.
dd8c1d6f-c3ed-464a-8c41-50bc9b1a0aad
Harris, Sarah E.
03e469e4-580c-4521-8d6c-2a015d23e832
Zhang, Qian
47c9e310-98dd-4b2f-bf2e-833962229d11
McRae, Allan F.
46a1761f-32cd-45a5-86c5-d782e94c7989
Hagenaars, Saskia P.
f5bef8aa-aeef-44bf-be77-43a1dd2dac9d
Hill, W. David
0db96a02-aefa-4e10-b013-1a00eba51ac5
Davies, Gail
8f2485ed-6813-4d29-bacd-2cca13301036
Ritchie, Craig W.
ffed2935-47d4-48c5-b1e9-bd7bbe759643
Gale, Catharine
5bb2abb3-7b53-42d6-8aa7-817e193140c8
Starr, John M.
efba1461-fa5a-4669-9801-d6530f48d01c
Goate, Alison M.
6ec2818d-abb7-4384-9315-4825e7640c15
Porteous, David J.
85b0f8c5-3005-46c9-bf2e-e1c7728fcf99
Yang, Jian
03ecc588-0dc4-448f-a669-7c7838f6bd46
Evans, Kathryn L.
2334b34e-bf25-46f7-a6dc-0e39adc10300
Deary, Ian J.
14b88084-7a90-44e4-9da9-1a332b7afafb
Wray, Naomi R.
2d7a050f-8e06-49a7-a68b-6561e2884f33
Visscher, Peter M.
dc99fabe-0039-4180-be9f-9d63b7485ca5
Marioni, Riccardo E.
dd8c1d6f-c3ed-464a-8c41-50bc9b1a0aad
Harris, Sarah E.
03e469e4-580c-4521-8d6c-2a015d23e832
Zhang, Qian
47c9e310-98dd-4b2f-bf2e-833962229d11
McRae, Allan F.
46a1761f-32cd-45a5-86c5-d782e94c7989
Hagenaars, Saskia P.
f5bef8aa-aeef-44bf-be77-43a1dd2dac9d
Hill, W. David
0db96a02-aefa-4e10-b013-1a00eba51ac5
Davies, Gail
8f2485ed-6813-4d29-bacd-2cca13301036
Ritchie, Craig W.
ffed2935-47d4-48c5-b1e9-bd7bbe759643
Gale, Catharine
5bb2abb3-7b53-42d6-8aa7-817e193140c8
Starr, John M.
efba1461-fa5a-4669-9801-d6530f48d01c
Goate, Alison M.
6ec2818d-abb7-4384-9315-4825e7640c15
Porteous, David J.
85b0f8c5-3005-46c9-bf2e-e1c7728fcf99
Yang, Jian
03ecc588-0dc4-448f-a669-7c7838f6bd46
Evans, Kathryn L.
2334b34e-bf25-46f7-a6dc-0e39adc10300
Deary, Ian J.
14b88084-7a90-44e4-9da9-1a332b7afafb
Wray, Naomi R.
2d7a050f-8e06-49a7-a68b-6561e2884f33
Visscher, Peter M.
dc99fabe-0039-4180-be9f-9d63b7485ca5
Marioni, Riccardo E., Harris, Sarah E., Zhang, Qian, McRae, Allan F., Hagenaars, Saskia P., Hill, W. David, Davies, Gail, Ritchie, Craig W., Gale, Catharine, Starr, John M., Goate, Alison M., Porteous, David J., Yang, Jian, Evans, Kathryn L., Deary, Ian J., Wray, Naomi R. and Visscher, Peter M.
(2018)
GWAS on family history of Alzheimer's disease.
Translational Psychiatry, 8, [99].
(doi:10.1038/s41398-018-0150-6).
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.
Text
s41398-018-0150-6
- Version of Record
More information
Accepted/In Press date: 4 April 2018
e-pub ahead of print date: 18 May 2018
Identifiers
Local EPrints ID: 421327
URI: http://eprints.soton.ac.uk/id/eprint/421327
PURE UUID: 74a37ae1-755a-4f18-88ab-9045c8f66a67
Catalogue record
Date deposited: 01 Jun 2018 16:30
Last modified: 16 Mar 2024 02:49
Export record
Altmetrics
Contributors
Author:
Riccardo E. Marioni
Author:
Sarah E. Harris
Author:
Qian Zhang
Author:
Allan F. McRae
Author:
Saskia P. Hagenaars
Author:
W. David Hill
Author:
Gail Davies
Author:
Craig W. Ritchie
Author:
John M. Starr
Author:
Alison M. Goate
Author:
David J. Porteous
Author:
Jian Yang
Author:
Kathryn L. Evans
Author:
Ian J. Deary
Author:
Naomi R. Wray
Author:
Peter M. Visscher
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics
