GWAS on family history of Alzheimer’s disease

Riccardo E. Marioni; Sarah E. Harris; Qian Zhang; Allan F. McRae; Saskia P. Hagenaars; W. David Hill; Gail Davies; Craig W. Ritchie; Catharine R. Gale; John M. Starr; Alison M. Goate; David J. Porteous; Jian Yang; Kathryn L. Evans; Ian J. Deary; Naomi R. Wray; Peter M. Visscher

doi:10.1038/s41398-018-0150-6

GWAS on family history of Alzheimer’s disease

Riccardo E. Marioni, Sarah E. Harris, Qian Zhang, Allan F. McRae, Saskia P. Hagenaars, W. David Hill, Gail Davies, Craig W. Ritchie, Catharine R. Gale, John M. Starr, Alison M. Goate, David J. Porteous, Jian Yang, Kathryn L. Evans, Ian J. Deary, Naomi R. Wray, Peter M. Visscher

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	99
Journal	Translational Psychiatry
Volume	8
DOIs	https://doi.org/10.1038/s41398-018-0150-6
Publication status	Published - 18 May 2018

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3 Finished

Omics prediction of Alzheimer's disease
Marioni, R. (Principal Investigator)
UK-based charities
1/10/17 → 31/01/21
Project: Research
MRC Dementias Platform
Deary, I. (Principal Investigator)
Other
1/04/14 → 31/03/20
Project: Research
RA2662 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.
Porteous, D. (Principal Investigator)
1/09/13 → 31/08/19
Project: Research

1 Comment/debate

Correction: GWAS on family history of Alzheimer’s disease
Marioni, R. E., Harris, S. E., Zhang, Q., Mcrae, A. F., Hagenaars, S. P., Hill, W. D., Davies, G., Ritchie, C. W., Gale, C. R., Starr, J. M., Goate, A. M., Porteous, D. J., Yang, J., Evans, K. L., Deary, I. J., Wray, N. R. & Visscher, P. M., 6 Jun 2019, In: Translational Psychiatry. 9, 1
Research output: Contribution to journal › Comment/debate

Open Access
File

Marioni_et_al_AD_GWAS_Sumstats_June2019_Correction - Data supporting Marioni et al. "GWAS on family history of Alzheimer's disease"
Marioni, R. (Creator), Gale, C. (Creator), Goate, A. (Creator), Porteous, D. (Creator), Yang, J. (Creator), Evans, K. (Creator), Deary, I. (Creator), Wray, N. R. (Creator), Visscher, P. (Creator), Starr, J. (Creator), Harris, S. (Creator), Zhang, Q. (Creator), Mcrae, A. F. (Creator), Hagenaars, S. (Creator), Hill, D. (Creator), Davies, G. (Creator) & Ritchie, C. (Creator), Edinburgh DataShare, 21 Jun 2019
DOI: 10.7488/ds/2578
Dataset

Riccardo Marioni
- Centre for Genomic and Experimental Medicine
- Edinburgh Neuroscience
- Institute of Genetics and Cancer - Personal Chair of Molecular Epidemiology of Ageing
- Institute of Genetics and Cancer
Person: Academic: Research Active

Cite this

Marioni, R. E., Harris, S. E., Zhang, Q., McRae, A. F., Hagenaars, S. P., Hill, W. D., Davies, G., Ritchie, C. W., Gale, C. R., Starr, J. M., Goate, A. M., Porteous, D. J., Yang, J., Evans, K. L., Deary, I. J., Wray, N. R., & Visscher, P. M. (2018). GWAS on family history of Alzheimer’s disease. Translational Psychiatry, 8, Article 99. https://doi.org/10.1038/s41398-018-0150-6

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title = "GWAS on family history of Alzheimer{\textquoteright}s disease",

abstract = "Alzheimer{\textquoteright}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{\textquoteright}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. ",

author = "Marioni, \{Riccardo E.\} and Harris, \{Sarah E.\} and Qian Zhang and McRae, \{Allan F.\} and Hagenaars, \{Saskia P.\} and Hill, \{W. David\} and Gail Davies and Ritchie, \{Craig W.\} and Gale, \{Catharine R.\} and Starr, \{John M.\} and Goate, \{Alison M.\} and Porteous, \{David J.\} and Jian Yang and Evans, \{Kathryn L.\} and Deary, \{Ian J.\} and Wray, \{Naomi R.\} and Visscher, \{Peter M.\}",

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doi = "10.1038/s41398-018-0150-6",

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T1 - GWAS on family history of Alzheimer’s disease

AU - Marioni, Riccardo E.

AU - Harris, Sarah E.

AU - Zhang, Qian

AU - McRae, Allan F.

AU - Hagenaars, Saskia P.

AU - Hill, W. David

AU - Davies, Gail

AU - Ritchie, Craig W.

AU - Gale, Catharine R.

AU - Starr, John M.

AU - Goate, Alison M.

AU - Porteous, David J.

AU - Yang, Jian

AU - Evans, Kathryn L.

AU - Deary, Ian J.

AU - Wray, Naomi R.

AU - Visscher, Peter M.

PY - 2018/5/18

Y1 - 2018/5/18

N2 - 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.

AB - 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.

U2 - 10.1038/s41398-018-0150-6

DO - 10.1038/s41398-018-0150-6

M3 - Article

SN - 2158-3188

VL - 8

JO - Translational Psychiatry

JF - Translational Psychiatry

M1 - 99

ER -

GWAS on family history of Alzheimer’s disease

Abstract

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Projects

Omics prediction of Alzheimer's disease

MRC Dementias Platform

RA2662 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.

Research output

Correction: GWAS on family history of Alzheimer’s disease

Datasets

Marioni_et_al_AD_GWAS_Sumstats_June2019_Correction - Data supporting Marioni et al. "GWAS on family history of Alzheimer's disease"

Profiles

Riccardo Marioni

Cite this