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; Børge 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, Børge 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 af dette arbejde

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Alzheimer's Disease
Vol/bind	88
Udgave nummer	4
Sider (fra-til)	1533-1544
Antal sider	12
ISSN	1387-2877
DOI	https://doi.org/10.3233/JAD-220174
Status	Udgivet - 2022

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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

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, bind 88, nr. 4, s. 1533-1544. https://doi.org/10.3233/JAD-220174

@article{77683d02b60b4d53b975badbb3b3b103,

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 = "Age of Onset, Alzheimer Disease/epidemiology, Genotype, Humans, Multifactorial Inheritance/genetics, Polymorphism, Single Nucleotide/genetics",

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, {B{\o}rge 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}",

year = "2022",

doi = "10.3233/JAD-220174",

language = "English",

volume = "88",

pages = "1533--1544",

journal = "Journal of Alzheimer's Disease",

issn = "1387-2877",

publisher = "I O S Press",

number = "4",

}

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, Børge 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

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 - Age of Onset

KW - Alzheimer Disease/epidemiology

KW - Genotype

KW - Humans

KW - Multifactorial Inheritance/genetics

KW - Polymorphism, Single Nucleotide/genetics

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U2 - 10.3233/JAD-220174

DO - 10.3233/JAD-220174

M3 - Journal 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

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