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

Article type: Research Article

Authors: Motazedi, Ehsan^a | Cheng, Weiqiu^a | Thomassen, Jesper Q.^b | Frei, Oleksandr^{a; c} | Rongve, Arvid^d | Athanasiu, Lavinia^a | Bahrami, Shahram^a | Shadrin, Alexey^a | Ulstein, Ingun^e | Stordal, Eystein^{f; g} | Brækhus, Anne^{e; h} | Saltvedt, Ingvild^{f; i} | Sando, Sigrid B.^{f; j} | O’Connell, Kevin S.^a | Hindley, Guy^{a; k} | van der Meer, Dennis^{a; l} | Bergh, Sverre^{m; n} | Nordestgaard, Børge G.^{o; p} | Tybjærg-Hansen, Anne^{b; o} | Bråthen, Geir^{f; j} | Pihlstrøm, Lasse^h | Djurovic, Srdjan^{q; r} | Frikke-Schmidt, Ruth^{b; o} | Fladby, Tormod^{f; s} | Aarsland, Dag^{t; u} | Selbæk, Geir^{e; n; v} | Seibert, Tyler M.^{a; w; x; y} | Dale, Anders M.^{w; x; z; aa} | Fan, Chun C.^{w; bb; cc} | Andreassen, Ole A.^{a; *}

Affiliations: [a] NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway | [b] Department of Clinical Biochemistry, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark | [c] Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway | [d] Department of Clinical Medicine, University of Bergen, Bergen, Norway | [e] Department of Geriatric Medicine, Oslo University Hospital, Ullevål, Oslo, Norway | [f] Department of Neuromedicine and Movement Science (INB), NTNU, Faculty of Medicine and Health Sciences, Trondheim, Norway | [g] Clinic of Psychiatry, Namsos Hospital, Namsos, Norway | [h] Department of Neurology, Oslo University Hospital, Oslo, Norway | [i] Department of Geriatric Medicine, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway | [j] Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway | [k] Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK | [l] School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands | [m] Research Center for Age-related Functional Decline and Disease, Innlandet Hospital Trust, Brumunddal, Norway | [n] Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway | [o] Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark | [p] Department of Clinical Biochemistry, Copenhagen University Hospital – Herlev Gentofte, Herlev, Denmark | [q] Department of Medical Genetics, Oslo University Hospital, Oslo, Norway | [r] NORMENT Centre, Department of Clinical Science, University of Bergen, Bergen, Norway | [s] Klinikk for Indremedisin og lab fag (AHUSKIL), Akershus University Hospital, Lørenskog, Norway | [t] Department of Old-Age Psychiatry, Stavanger University Hospital, Stavanger, Norway | [u] Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK | [v] Faculty of Medicine, University of Oslo, Oslo, Norway | [w] Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA | [x] Department of Radiology, University of California San Diego, La Jolla, CA, USA | [y] Department of Bioengineering, University of California San Diego, La Jolla, CA | [z] Department of Psychiatry, University of California San Diego, La Jolla, CA, USA | [aa] Department of Neurosciences, University of California San Diego, La Jolla, CA, USA | [bb] Department of Cognitive Science, University of California San Diego, La Jolla, CA, USA | [cc] Population Neuroscience and Genetics Lab, University of California San Diego, La Jolla, CA, USA

Correspondence: [*] Correspondence to: Ole A. Andreassen, MD, PhD, NORMENT, Ullevål Hospital, building 49, P.O. Box 4956 Nydalen, N-0424 Oslo, Norway. Tel.: +47 23 02 73 50; Fax: +47 23 02 73 33; E-mail: [email protected].

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.

Keywords: Age at onset, Alzheimer’s disease, Nordic ancestry, polygenic hazard score

DOI: 10.3233/JAD-220174

Journal: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1533-1544, 2022