Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer's Disease in Nordic Populations

Ehsan Motazedi, Weiqiu Cheng, Jesper Q. Thomassen, Oleksandr Frei, Arvid Rongve, Lavinia Athanasiu, Shahram Bahrami, Alexey Shadrin, Ingun Ulstein, Eystein Stordal, Anne Brækhus, Ingvild Saltvedt, Sigrid B. Sando, Kevin S. O'Connell, Guy Hindley, Dennis van der Meer, Sverre Bergh, Brge G. Nordestgaard, Anne Tybjærg-Hansen, Geir BrthenLasse Pihlstrm, Srdjan Djurovic, Ruth Frikke-Schmidt, Tormod Fladby, Dag Aarsland, Geir Selbæk, Tyler M. Seibert, Anders M. Dale, Chun C. Fan, Ole A. Andreassen

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

BACKGROUND: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer's disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. OBJECTIVE: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. METHODS: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian DemGene cohort (n = 2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (n = 7,643) and The Copenhagen General Population Study (CGPS) cohort (n = 10,886). RESULTS: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. CONCLUSION: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations.

Original languageEnglish
Pages (from-to)1533-1544
Number of pages12
JournalJournal of Alzheimer's disease : JAD
Volume88
Issue number4
DOIs
Publication statusPublished - 16 Aug 2022

Keywords

  • Age at onset
  • Alzheimer’s disease
  • Nordic ancestry
  • polygenic hazard score

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