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

Age of Onset Alzheimer Disease / epidemiology Genotype Humans Multifactorial Inheritance / genetics Polymorphism, Single Nucleotide / genetics
Age at onset Alzheimer’s disease Nordic ancestry polygenic hazard score

Journal

Journal of Alzheimer's disease : JAD
ISSN: 1875-8908
Titre abrégé: J Alzheimers Dis
Pays: Netherlands
ID NLM: 9814863

Informations de publication

Date de publication:
2022
Historique:
pubmed: 19 7 2022
medline: 24 8 2022
entrez: 18 7 2022
Statut: ppublish

Résumé

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. The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. 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). 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.3233/JAD-220174 PMID: 35848024 PMC: PMC10022308
pubmed: 35848024
pii: JAD220174
doi: 10.3233/JAD-220174
pmc: PMC10022308
mid: NIHMS1867056
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

1533-1544

Subventions

Organisme : NIBIB NIH HHS
ID : K08 EB026503
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG017560
Pays : United States

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Auteurs

Ehsan Motazedi (E)

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

Weiqiu Cheng (W)

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

Jesper Q Thomassen (JQ)

Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

Oleksandr Frei (O)

NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.

Arvid Rongve (A)

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

Lavinia Athanasiu (L)

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

Shahram Bahrami (S)

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

Alexey Shadrin (A)

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

Ingun Ulstein (I)

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

Eystein Stordal (E)

Department of Neuromedicine and Movement Science (INB), NTNU, Faculty of Medicine and Health Sciences, Trondheim, Norway.
Clinic of Psychiatry, Namsos Hospital, Namsos, Norway.

Anne Brækhus (A)

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

Ingvild Saltvedt (I)

Department of Neuromedicine and Movement Science (INB), NTNU, Faculty of Medicine and Health Sciences, Trondheim, Norway.
Department of Geriatric Medicine, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Sigrid B Sando (SB)

Department of Neuromedicine and Movement Science (INB), NTNU, Faculty of Medicine and Health Sciences, Trondheim, Norway.
Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway.

Kevin S O'Connell (KS)

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

Guy Hindley (G)

NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Dennis van der Meer (D)

NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.

Sverre Bergh (S)

Research Center for Age-related Functional Decline and Disease, Innlandet Hospital Trust, Brumunddal, Norway.
Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.

Børge G Nordestgaard (BG)

Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev Gentofte, Herlev, Denmark.

Anne Tybjærg-Hansen (A)

Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Geir Bråthen (G)

Department of Neuromedicine and Movement Science (INB), NTNU, Faculty of Medicine and Health Sciences, Trondheim, Norway.
Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway.

Lasse Pihlstrøm (L)

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

Srdjan Djurovic (S)

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
NORMENT Centre, Department of Clinical Science, University of Bergen, Bergen, Norway.

Ruth Frikke-Schmidt (R)

Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Tormod Fladby (T)

Department of Neuromedicine and Movement Science (INB), NTNU, Faculty of Medicine and Health Sciences, Trondheim, Norway.
Klinikk for Indremedisin og lab fag (AHUSKIL), Akershus University Hospital, Lørenskog, Norway.

Dag Aarsland (D)

Department of Old-Age Psychiatry, Stavanger University Hospital, Stavanger, Norway.
Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Geir Selbæk (G)

Department of Geriatric Medicine, Oslo University Hospital, Ullevål, Oslo, Norway.
Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
Faculty of Medicine, University of Oslo, Oslo, Norway.

Tyler M Seibert (TM)

NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
Department of Radiology, University of California San Diego, La Jolla, CA, USA.
Department of Bioengineering, University of California San Diego, La Jolla, CA.

Anders M Dale (AM)

Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
Department of Radiology, University of California San Diego, La Jolla, CA, USA.
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.

Chun C Fan (CC)

Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
Department of Cognitive Science, University of California San Diego, La Jolla, CA, USA.
Population Neuroscience and Genetics Lab, University of California San Diego, La Jolla, CA, USA.

Ole A Andreassen (OA)

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

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Classifications MeSH

questionsmedicales.fr › Environnement et santé publique › Santé publique › Facteurs épidémiologiques › Facteurs âges › Âge de début › Using Polygenic Hazard Scores to Predict Age...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › Using Polygenic Hazard Scores to Predict Age...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Using Polygenic Hazard Scores to Predict Age...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Using Polygenic Hazard Scores to Predict Age...
questionsmedicales.fr › Phénomènes génétiques › Modes de transmission héréditaire › Hérédité multifactorielle › Using Polygenic Hazard Scores to Predict Age...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Using Polygenic Hazard Scores to Predict Age...