PLoS Medicine (Mar 2017)

Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score.

  • Rahul S Desikan,
  • Chun Chieh Fan,
  • Yunpeng Wang,
  • Andrew J Schork,
  • Howard J Cabral,
  • L Adrienne Cupples,
  • Wesley K Thompson,
  • Lilah Besser,
  • Walter A Kukull,
  • Dominic Holland,
  • Chi-Hua Chen,
  • James B Brewer,
  • David S Karow,
  • Karolina Kauppi,
  • Aree Witoelar,
  • Celeste M Karch,
  • Luke W Bonham,
  • Jennifer S Yokoyama,
  • Howard J Rosen,
  • Bruce L Miller,
  • William P Dillon,
  • David M Wilson,
  • Christopher P Hess,
  • Margaret Pericak-Vance,
  • Jonathan L Haines,
  • Lindsay A Farrer,
  • Richard Mayeux,
  • John Hardy,
  • Alison M Goate,
  • Bradley T Hyman,
  • Gerard D Schellenberg,
  • Linda K McEvoy,
  • Ole A Andreassen,
  • Anders M Dale

DOI
https://doi.org/10.1371/journal.pmed.1002258
Journal volume & issue
Vol. 14, no. 3
p. e1002258

Abstract

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BackgroundIdentifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction.Methods and findingsUsing genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1), we identified AD-associated SNPs (at p ConclusionsWe have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials.