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 Brthen; Lasse Pihlstrm; Srdjan Djurovic; Ruth Frikke-Schmidt; Tormod Fladby; Dag Aarsland; Geir Selbæk; Tyler M Seibert; Anders M Dale; Chun C Fan; Ole A Andreassen

doi:10.3233/JAD-220174

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	1533-1544
Number of pages	12
Journal	Journal of Alzheimer's Disease
Volume	88
Issue number	4
Early online date	7 Jul 2022
DOIs	https://doi.org/10.3233/JAD-220174
Publication status	Published - 2022

Keywords

APOLIPOPROTEIN-E
ASSOCIATION
Age at onset
Alzheimer's disease
DEMENTIA
GENOTYPE
HAPLOTYPES
LINKAGE
Nordic ancestry
PROGRESSION
RISK
TYPE-4 ALLELE
VARIANTS
polygenic hazard score

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10.3233/JAD-220174

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Motazedi, E., Cheng, W., Thomassen, J. Q., Frei, O., Rongve, A., Athanasiu, L., Bahrami, S., Shadrin, A., Ulstein, I., Stordal, E., Brækhus, A., Saltvedt, I., Sando, S. B., O'Connell, K. S., Hindley, G., van der Meer, D., Bergh, S., Nordestgaard, B. G., Tybjærg-Hansen, A., ... Andreassen, O. A. (2022). Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer's Disease in Nordic Populations. Journal of Alzheimer's Disease, 88(4), 1533-1544. https://doi.org/10.3233/JAD-220174

@article{edeabec544e947d39e47fb9a8909db2a,

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

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 = "APOLIPOPROTEIN-E, ASSOCIATION, Age at onset, Alzheimer's disease, DEMENTIA, GENOTYPE, HAPLOTYPES, LINKAGE, Nordic ancestry, PROGRESSION, RISK, TYPE-4 ALLELE, VARIANTS, polygenic hazard score",

author = "Ehsan Motazedi and Weiqiu Cheng and Thomassen, {Jesper Q} and Oleksandr Frei and Arvid Rongve and Lavinia Athanasiu and Shahram Bahrami and Alexey Shadrin and Ingun Ulstein and Eystein Stordal and Anne Br{\ae}khus and Ingvild Saltvedt and Sando, {Sigrid B} and O'Connell, {Kevin S} and Guy Hindley and {van der Meer}, Dennis and Sverre Bergh and Nordestgaard, {Brge G} and Anne Tybj{\ae}rg-Hansen and Geir Brthen and Lasse Pihlstrm and Srdjan Djurovic and Ruth Frikke-Schmidt and Tormod Fladby and Dag Aarsland and Geir Selb{\ae}k and Seibert, {Tyler M} and Dale, {Anders M} and Fan, {Chun C} and Andreassen, {Ole A}",

note = "Funding Information: The authors would like to thank the participants of the Norwegian Dementia Genetics Network (DemGene) and the clinical units involved in data collection, as well as the participants and staff of the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS) for their important contributions. EM and WC received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement No 801133. The other authors were funded by the Research Council of Norway (OAA: 213837, 223273, 229129, 248778, 248980, 262656, 273291, 283798, 311993), the South-Eastern Norway Regional Health Authority (OAA: 2013–123, 2017–112, 2019–108, 2020–034), National Institute on Aging (R01 AG08724, R01 AG17561, R01 AG028555, R01 AG060470), EU JPND: PMI-AD RCN 311993 and the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant #847776 CoMorMent). We gratefully acknowledge support from the American National Institute of Health (NS057198, EB00790), KG Jebsen Stiftelsen, and the Norwegian Health Association (22731). The CCHS and CGPS studies were funded by the Danish Heart Association, the Danish Lung Association, the Velux Foundation, and the Lundbeck Foundation. Publisher Copyright: {\textcopyright} 2022 - IOS Press. All rights reserved.",

year = "2022",

doi = "10.3233/JAD-220174",

language = "English",

volume = "88",

pages = "1533--1544",

journal = "Journal of Alzheimer's Disease",

issn = "1387-2877",

publisher = "IOS Press",

number = "4",

}

Motazedi, E, Cheng, W, Thomassen, JQ, Frei, O, Rongve, A, Athanasiu, L, Bahrami, S, Shadrin, A, Ulstein, I, Stordal, E, Brækhus, A, Saltvedt, I, Sando, SB, O'Connell, KS, Hindley, G, van der Meer, D, Bergh, S, Nordestgaard, BG, Tybjærg-Hansen, A, Brthen, G, Pihlstrm, L, Djurovic, S, Frikke-Schmidt, R, Fladby, T, Aarsland, D, Selbæk, G, Seibert, TM, Dale, AM, Fan, CC & Andreassen, OA 2022, 'Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer's Disease in Nordic Populations', Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1533-1544. https://doi.org/10.3233/JAD-220174

TY - JOUR

T1 - Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer's Disease in Nordic Populations

AU - Motazedi, Ehsan

AU - Cheng, Weiqiu

AU - Thomassen, Jesper Q

AU - Frei, Oleksandr

AU - Rongve, Arvid

AU - Athanasiu, Lavinia

AU - Bahrami, Shahram

AU - Shadrin, Alexey

AU - Ulstein, Ingun

AU - Stordal, Eystein

AU - Brækhus, Anne

AU - Saltvedt, Ingvild

AU - Sando, Sigrid B

AU - O'Connell, Kevin S

AU - Hindley, Guy

AU - van der Meer, Dennis

AU - Bergh, Sverre

AU - Nordestgaard, Brge G

AU - Tybjærg-Hansen, Anne

AU - Brthen, Geir

AU - Pihlstrm, Lasse

AU - Djurovic, Srdjan

AU - Frikke-Schmidt, Ruth

AU - Fladby, Tormod

AU - Aarsland, Dag

AU - Selbæk, Geir

AU - Seibert, Tyler M

AU - Dale, Anders M

AU - Fan, Chun C

AU - Andreassen, Ole A

N1 - Funding Information: The authors would like to thank the participants of the Norwegian Dementia Genetics Network (DemGene) and the clinical units involved in data collection, as well as the participants and staff of the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS) for their important contributions. EM and WC received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 801133. The other authors were funded by the Research Council of Norway (OAA: 213837, 223273, 229129, 248778, 248980, 262656, 273291, 283798, 311993), the South-Eastern Norway Regional Health Authority (OAA: 2013–123, 2017–112, 2019–108, 2020–034), National Institute on Aging (R01 AG08724, R01 AG17561, R01 AG028555, R01 AG060470), EU JPND: PMI-AD RCN 311993 and the European Union’s Horizon 2020 research and innovation program (grant #847776 CoMorMent). We gratefully acknowledge support from the American National Institute of Health (NS057198, EB00790), KG Jebsen Stiftelsen, and the Norwegian Health Association (22731). The CCHS and CGPS studies were funded by the Danish Heart Association, the Danish Lung Association, the Velux Foundation, and the Lundbeck Foundation. Publisher Copyright: © 2022 - IOS Press. All rights reserved.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - APOLIPOPROTEIN-E

KW - ASSOCIATION

KW - Age at onset

KW - Alzheimer's disease

KW - DEMENTIA

KW - GENOTYPE

KW - HAPLOTYPES

KW - LINKAGE

KW - Nordic ancestry

KW - PROGRESSION

KW - RISK

KW - TYPE-4 ALLELE

KW - VARIANTS

KW - polygenic hazard score

U2 - 10.3233/JAD-220174

DO - 10.3233/JAD-220174

M3 - Article

C2 - 35848024

SN - 1387-2877

VL - 88

SP - 1533

EP - 1544

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

IS - 4

ER -

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

Abstract

Keywords

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