GWAS on family history of Alzheimer's disease

doi:10.1038/s41398-018-0150-6

. 2018 May 18;8(1):99.

doi: 10.1038/s41398-018-0150-6.

GWAS on family history of Alzheimer's disease

Riccardo E Marioni^{1

2}, Sarah E Harris^{3

4}, Qian Zhang⁵, Allan F McRae⁵, Saskia P Hagenaars^{4

6}, W David Hill^{4

7}, Gail Davies⁴, Craig W Ritchie⁸, Catharine R Gale^{4

7

9}, John M Starr^{4

10}, Alison M Goate¹¹, David J Porteous^{3

4}, Jian Yang^{5

12}, Kathryn L Evans³, Ian J Deary^{4

7}, Naomi R Wray^{5

12}, Peter M Visscher^{4

5

12}

Affiliations

¹ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK. riccardo.marioni@ed.ac.uk.
² Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. riccardo.marioni@ed.ac.uk.
³ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
⁴ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
⁵ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
⁶ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE5 8AF, UK.
⁷ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
⁸ Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH8 9YL, UK.
⁹ MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, SO16 6YD, UK.
¹⁰ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
¹¹ 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, 10029-5674, USA.
¹² Queensland Brain Institute, University of Queensland, Brisbane, QLD, 4072, Australia.

PMID: 29777097
PMCID: PMC5959890
DOI: 10.1038/s41398-018-0150-6

GWAS on family history of Alzheimer's disease

Riccardo E Marioni et al. Transl Psychiatry. 2018.

. 2018 May 18;8(1):99.

doi: 10.1038/s41398-018-0150-6.

Authors

Affiliations

¹ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK. riccardo.marioni@ed.ac.uk.
² Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. riccardo.marioni@ed.ac.uk.
³ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
⁴ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
⁵ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
⁶ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE5 8AF, UK.
⁷ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
⁸ Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH8 9YL, UK.
⁹ MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, SO16 6YD, UK.
¹⁰ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
¹¹ 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, 10029-5674, USA.
¹² Queensland Brain Institute, University of Queensland, Brisbane, QLD, 4072, Australia.

PMID: 29777097
PMCID: PMC5959890
DOI: 10.1038/s41398-018-0150-6

Erratum in

Correction: GWAS on family history of Alzheimer's disease.
Marioni RE, Harris SE, Zhang Q, McRae AF, Hagenaars SP, Hill WD, Davies G, Ritchie CW, Gale CR, Starr JM, Goate AM, Porteous DJ, Yang J, Evans KL, Deary IJ, Wray NR, Visscher PM. Marioni RE, et al. Transl Psychiatry. 2019 Jun 6;9(1):161. doi: 10.1038/s41398-019-0498-2. Transl Psychiatry. 2019. PMID: 31171767 Free PMC article.

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.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

**Fig. 1. Manhattan plot for the meta-analysis of maternal and paternal Alzheimer’s disease in UK Biobank and the results from stage 1 and stage 2 of IGAP.**
The red line indicates P = 5 × 10⁻⁸ and the blue line indicates P = 1 × 10⁻⁵. P-values truncated at 1 × 10⁻²⁰

See this image and copyright information in PMC

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References

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1. Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet. Med. 2016;18:421–430. doi: 10.1038/gim.2015.117. - DOI - PMC - PubMed
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1. Sibbett RA, Russ TC, Deary IJ, Starr JM. Dementia ascertainment using existing data in UK longitudinal and cohort studies: a systematic review of methodology. BMC Psychiatry. 2017;17:239. doi: 10.1186/s12888-017-1401-4. - DOI - PMC - PubMed
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[1] Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148:1204–1222. doi: 10.1016/j.cell.2012.02.040. - DOI - PMC - PubMed

[2] Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148:1204–1222. doi: 10.1016/j.cell.2012.02.040. - DOI - PMC - PubMed

[3] Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet. Med. 2016;18:421–430. doi: 10.1038/gim.2015.117. - DOI - PMC - PubMed

[4] Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet. Med. 2016;18:421–430. doi: 10.1038/gim.2015.117. - DOI - PMC - PubMed

[5] Lambert JC, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 2013;45:1452–1458. doi: 10.1038/ng.2802. - DOI - PMC - PubMed

[6] Lambert JC, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 2013;45:1452–1458. doi: 10.1038/ng.2802. - DOI - PMC - PubMed

[7] Sibbett RA, Russ TC, Deary IJ, Starr JM. Dementia ascertainment using existing data in UK longitudinal and cohort studies: a systematic review of methodology. BMC Psychiatry. 2017;17:239. doi: 10.1186/s12888-017-1401-4. - DOI - PMC - PubMed

[8] Sibbett RA, Russ TC, Deary IJ, Starr JM. Dementia ascertainment using existing data in UK longitudinal and cohort studies: a systematic review of methodology. BMC Psychiatry. 2017;17:239. doi: 10.1186/s12888-017-1401-4. - DOI - PMC - PubMed

[9] Liu JZ, Erlich Y, Pickrell JK. Case-control association mapping by proxy using family history of 363 disease. Nat. Genet. 2017;49:325–331. doi: 10.1038/ng.3766. - DOI - PubMed

[10] Liu JZ, Erlich Y, Pickrell JK. Case-control association mapping by proxy using family history of 363 disease. Nat. Genet. 2017;49:325–331. doi: 10.1038/ng.3766. - DOI - PubMed

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GWAS on family history of Alzheimer's disease

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GWAS on family history of Alzheimer's disease

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