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

Author:

Motazedi Ehsan1,Cheng Weiqiu1,Thomassen Jesper Q.2,Frei Oleksandr13,Rongve Arvid4,Athanasiu Lavinia1,Bahrami Shahram1,Shadrin Alexey1,Ulstein Ingun5,Stordal Eystein67,Brækhus Anne58,Saltvedt Ingvild69,Sando Sigrid B.610,O’Connell Kevin S.1,Hindley Guy111,van der Meer Dennis112,Bergh Sverre1314,Nordestgaard Børge G.1516,Tybjærg-Hansen Anne215,Bråthen Geir610,Pihlstrøm Lasse8,Djurovic Srdjan1718,Frikke-Schmidt Ruth215,Fladby Tormod619,Aarsland Dag2021,Selbæk Geir51422,Seibert Tyler M.1232425,Dale Anders M.23242627,Fan Chun C.232829,Andreassen Ole A.1

Affiliation:

1. NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

2. Department of Clinical Biochemistry, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark

3. Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway

4. Department of Clinical Medicine, University of Bergen, Bergen, Norway

5. Department of Geriatric Medicine, Oslo University Hospital, Ullevål, Oslo, Norway

6. Department of Neuromedicine and Movement Science (INB), NTNU, Faculty of Medicine and Health Sciences, Trondheim, Norway

7. Clinic of Psychiatry, Namsos Hospital, Namsos, Norway

8. Department of Neurology, Oslo University Hospital, Oslo, Norway

9. Department of Geriatric Medicine, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

10. Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway

11. Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

12. School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands

13. Research Center for Age-related Functional Decline and Disease, Innlandet Hospital Trust, Brumunddal, Norway

14. Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway

15. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

16. Department of Clinical Biochemistry, Copenhagen University Hospital – Herlev Gentofte, Herlev, Denmark

17. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

18. NORMENT Centre, Department of Clinical Science, University of Bergen, Bergen, Norway

19. Klinikk for Indremedisin og lab fag (AHUSKIL), Akershus University Hospital, Lørenskog, Norway

20. Department of Old-Age Psychiatry, Stavanger University Hospital, Stavanger, Norway

21. Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

22. Faculty of Medicine, University of Oslo, Oslo, Norway

23. Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA

24. Department of Radiology, University of California San Diego, La Jolla, CA, USA

25. Department of Bioengineering, University of California San Diego, La Jolla, CA

26. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

27. Department of Neurosciences, University of California San Diego, La Jolla, CA, USA

28. Department of Cognitive Science, University of California San Diego, La Jolla, CA, USA

29. Population Neuroscience and Genetics Lab, University of California San Diego, La Jolla, CA, USA

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.

Publisher

IOS Press

Subject

Psychiatry and Mental health,Geriatrics and Gerontology,Clinical Psychology,General Medicine,General Neuroscience

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3