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Genome-wide association analysis of age-at-onset in Alzheimer's disease

Molecular Psychiatry volume 17, pages 1340–1346 (2012)Cite this article

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Abstract

The risk of Alzheimer's disease (AD) is strongly determined by genetic factors and recent genome-wide association studies (GWAS) have identified several genes for the disease risk. In addition to the disease risk, age-at-onset (AAO) of AD has also strong genetic component with an estimated heritability of 42%. Identification of AAO genes may help to understand the biological mechanisms that regulate the onset of the disease. Here we report the first GWAS focused on identifying genes for the AAO of AD. We performed a genome-wide meta-analysis on three samples comprising a total of 2222 AD cases. A total of ∼2.5 million directly genotyped or imputed single-nucleotide polymorphisms (SNPs) were analyzed in relation to AAO of AD. As expected, the most significant associations were observed in the apolipoprotein E (APOE) region on chromosome 19 where several SNPs surpassed the conservative genome-wide significant threshold (P<5E-08). The most significant SNP outside the APOE region was located in the DCHS2 gene on chromosome 4q31.3 (rs1466662; P=4.95E-07). There were 19 additional significant SNPs in this region at P<1E-04 and the DCHS2 gene is expressed in the cerebral cortex and thus is a potential candidate for affecting AAO in AD. These findings need to be confirmed in additional well-powered samples.

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Acknowledgements

This study was supported by the National Institute on Aging grants AG030653 (MIK), AG005133 (ADRC), AG027224 (RAS) and AG18023 (SGY). We thank Drs Peter Gregersen and Annette Lee of the Feinstein Institute of Medical Research where the genotyping of the discovery sample was performed. We acknowledge Drs Neill R Graff-Radford, Dennis W Dickson and Ronald C Petersen for their key contribution in collecting the Mayo replication sample. One of the replication data sets was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904; RC2 AG036535). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co, Medpace, Inc, Merck and Co, Inc, Novartis AG, Pfizer Inc, F Hoffman-La Roche, Schering-Plough, Synarc, Inc, as well as non-profit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514 and the Dana Foundation. Some sample collection was supported by the NIA National Cell Repository for Alzheimer's Disease (NCRAD; U24 AG021886) and additional support for data analysis was provided by R01 AG19771 and P30 AG10133. We thank the following people for their contributions to the ADNI genotyping project: Tatiana Foroud, Kelley Faber, Li Shen, Steven G Potkin, Matthew J Huentelman, David W Craig, Sungeun Kim, Kwangsik Nho and Bryan M DeChairo.

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Authors and Affiliations

  1. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    M I Kamboh, M M Barmada, F Y Demirci, R L Minster & E Feingold

  2. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA

    M M Carrasquillo, V S Pankratz & S G Younkin

  3. Departments of Radiology and Imaging Sciences and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    A J Saykin

  4. Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    R A Sweet

  5. Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    R A Sweet & O L Lopez

  6. Office of the Dean and Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA

    S T DeKosky

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  1. M I Kamboh
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The Alzheimer's Disease Neuroimaging Initiative

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Correspondence to M I Kamboh.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Appendix

Appendix

Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (http://www.adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data, but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Authorship_List.pdf

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Kamboh, M., Barmada, M., Demirci, F. et al. Genome-wide association analysis of age-at-onset in Alzheimer's disease. Mol Psychiatry 17, 1340–1346 (2012). https://doi.org/10.1038/mp.2011.135

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