Dataset Information

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

ABSTRACT:

Background

We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.

Materials and methods

Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.

Results

CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.

Conclusion

We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

SUBMITTER: Karunamuni RA

PROVIDER: S-EPMC8669040 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

Karunamuni Roshan A RA Huynh-Le Minh-Phuong MP Fan Chun C CC Thompson Wesley W Lui Asona A Martinez Maria Elena ME Rose Brent S BS Mahal Brandon B Eeles Rosalind A RA Kote-Jarai Zsofia Z Muir Kenneth K Lophatananon Artitaya A Tangen Catherine M CM Goodman Phyllis J PJ Thompson Ian M IM Blot William J WJ Zheng Wei W Kibel Adam S AS Drake Bettina F BF Cussenot Olivier O Cancel-Tassin Géraldine G Menegaux Florence F Truong Thérèse T Park Jong Y JY Lin Hui-Yi HY Taylor Jack A JA Bensen Jeannette T JT Mohler James L JL Fontham Elizabeth T H ETH Multigner Luc L Blanchet Pascal P Brureau Laurent L Romana Marc M Leach Robin J RJ John Esther M EM Fowke Jay H JH Bush William S WS Aldrich Melinda C MC Crawford Dana C DC Cullen Jennifer J Petrovics Gyorgy G Parent Marie-Élise MÉ Hu Jennifer J JJ Sanderson Maureen M Mills Ian G IG Andreassen Ole A OA Dale Anders M AM Seibert Tyler M TM

Prostate cancer and prostatic diseases 20210614 2

<h4>Background</h4>We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.<h4>Materials and ...[more]

PMID: 34127801

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Project description:Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-β protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 non-demented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia.

Dataset Information

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

Background

Materials and methods

Results

Conclusion

Publications

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

Similar Datasets

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