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Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson’s disease cohort

BACKGROUND: Large-scale Parkinson’s disease (PD) genome-wide association studies (GWAS) have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European...

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Autores principales: Loesch, Douglas P., Horimoto, Andrea R.V.R., Sarihan, Elif Irem, Inca-Martinez, Miguel, Mason, Emily, Cornejo-Olivas, Mario, Torres, Luis, Mazzetti, Pilar, Cosentino, Carlos, Sarapura-Castro, Elison, Rivera-Valdivia, Andrea, Medina, Angel C., Dieguez, Elena, Raggio, Victor, Lescano, Andres, Tumas, Vitor, Borges, Vanderci, Ferraz, Henrique B., Rieder, Carlos R., Schumacher-Schuh, Artur, Santos-Lobato, Bruno L., Velez-Pardo, Carlos, Jimenez-Del-Rio, Marlene, Lopera, Francisco, Moreno, Sonia, Chana-Cuevas, Pedro, Fernandez, William, Arboleda, Gonzalo, Arboleda, Humberto, Arboleda-Bustos, Carlos E., Yearout, Dora, Zabetian, Cyrus P., Thornton, Timothy A., Mata, Ignacio F., O’Connor, Timothy D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10112543/
https://www.ncbi.nlm.nih.gov/pubmed/35917738
http://dx.doi.org/10.1016/j.parkreldis.2022.06.010
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author Loesch, Douglas P.
Horimoto, Andrea R.V.R.
Sarihan, Elif Irem
Inca-Martinez, Miguel
Mason, Emily
Cornejo-Olivas, Mario
Torres, Luis
Mazzetti, Pilar
Cosentino, Carlos
Sarapura-Castro, Elison
Rivera-Valdivia, Andrea
Medina, Angel C.
Dieguez, Elena
Raggio, Victor
Lescano, Andres
Tumas, Vitor
Borges, Vanderci
Ferraz, Henrique B.
Rieder, Carlos R.
Schumacher-Schuh, Artur
Santos-Lobato, Bruno L.
Velez-Pardo, Carlos
Jimenez-Del-Rio, Marlene
Lopera, Francisco
Moreno, Sonia
Chana-Cuevas, Pedro
Fernandez, William
Arboleda, Gonzalo
Arboleda, Humberto
Arboleda-Bustos, Carlos E.
Yearout, Dora
Zabetian, Cyrus P.
Thornton, Timothy A.
Mata, Ignacio F.
O’Connor, Timothy D.
author_facet Loesch, Douglas P.
Horimoto, Andrea R.V.R.
Sarihan, Elif Irem
Inca-Martinez, Miguel
Mason, Emily
Cornejo-Olivas, Mario
Torres, Luis
Mazzetti, Pilar
Cosentino, Carlos
Sarapura-Castro, Elison
Rivera-Valdivia, Andrea
Medina, Angel C.
Dieguez, Elena
Raggio, Victor
Lescano, Andres
Tumas, Vitor
Borges, Vanderci
Ferraz, Henrique B.
Rieder, Carlos R.
Schumacher-Schuh, Artur
Santos-Lobato, Bruno L.
Velez-Pardo, Carlos
Jimenez-Del-Rio, Marlene
Lopera, Francisco
Moreno, Sonia
Chana-Cuevas, Pedro
Fernandez, William
Arboleda, Gonzalo
Arboleda, Humberto
Arboleda-Bustos, Carlos E.
Yearout, Dora
Zabetian, Cyrus P.
Thornton, Timothy A.
Mata, Ignacio F.
O’Connor, Timothy D.
author_sort Loesch, Douglas P.
collection PubMed
description BACKGROUND: Large-scale Parkinson’s disease (PD) genome-wide association studies (GWAS) have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts. METHODS: Using GWAS data from the largest study to date, we constructed a PD PRS for a Latino PD cohort (1497 subjects from LARGE-PD) and tested it for association with PD status and age at onset. We validated the PRS performance by testing it in an independent Latino cohort (448 subjects) and by repeating the analysis in LARGE-PD with the addition of 440 external Peruvian controls. We also tested SNCA haplotypes for association with PD risk in LARGE-PD and a European-ancestry PD cohort. RESULTS: The GWAS-significant PD PRS had an area under the receiver-operator curve (AUC) of 0.668 (95% CI: 0.640–0.695) in LARGE-PD. The inclusion of external Peruvian controls mitigated this result, dropping the AUC 0.632 (95% CI: 0.607–0.657). At the SNCA locus, haplotypes differ by ancestry. Ancestry-specific SNCA haplotypes were associated with PD status in both LARGE-PD and the European-ancestry cohort (p-value < 0.05). These haplotypes both include the rs356182 G-allele, but only share 14% of their variants overall. CONCLUSION: The PD PRS has potential for PD risk prediction in Latinos, but variability caused by admixture patterns and bias in a European-ancestry PD PRS data limits its utility. The inclusion of diverse subjects can help elucidate PD risk loci and improve risk prediction in non-European cohorts.
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spelling pubmed-101125432023-09-01 Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson’s disease cohort Loesch, Douglas P. Horimoto, Andrea R.V.R. Sarihan, Elif Irem Inca-Martinez, Miguel Mason, Emily Cornejo-Olivas, Mario Torres, Luis Mazzetti, Pilar Cosentino, Carlos Sarapura-Castro, Elison Rivera-Valdivia, Andrea Medina, Angel C. Dieguez, Elena Raggio, Victor Lescano, Andres Tumas, Vitor Borges, Vanderci Ferraz, Henrique B. Rieder, Carlos R. Schumacher-Schuh, Artur Santos-Lobato, Bruno L. Velez-Pardo, Carlos Jimenez-Del-Rio, Marlene Lopera, Francisco Moreno, Sonia Chana-Cuevas, Pedro Fernandez, William Arboleda, Gonzalo Arboleda, Humberto Arboleda-Bustos, Carlos E. Yearout, Dora Zabetian, Cyrus P. Thornton, Timothy A. Mata, Ignacio F. O’Connor, Timothy D. Parkinsonism Relat Disord Article BACKGROUND: Large-scale Parkinson’s disease (PD) genome-wide association studies (GWAS) have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts. METHODS: Using GWAS data from the largest study to date, we constructed a PD PRS for a Latino PD cohort (1497 subjects from LARGE-PD) and tested it for association with PD status and age at onset. We validated the PRS performance by testing it in an independent Latino cohort (448 subjects) and by repeating the analysis in LARGE-PD with the addition of 440 external Peruvian controls. We also tested SNCA haplotypes for association with PD risk in LARGE-PD and a European-ancestry PD cohort. RESULTS: The GWAS-significant PD PRS had an area under the receiver-operator curve (AUC) of 0.668 (95% CI: 0.640–0.695) in LARGE-PD. The inclusion of external Peruvian controls mitigated this result, dropping the AUC 0.632 (95% CI: 0.607–0.657). At the SNCA locus, haplotypes differ by ancestry. Ancestry-specific SNCA haplotypes were associated with PD status in both LARGE-PD and the European-ancestry cohort (p-value < 0.05). These haplotypes both include the rs356182 G-allele, but only share 14% of their variants overall. CONCLUSION: The PD PRS has potential for PD risk prediction in Latinos, but variability caused by admixture patterns and bias in a European-ancestry PD PRS data limits its utility. The inclusion of diverse subjects can help elucidate PD risk loci and improve risk prediction in non-European cohorts. 2022-09 2022-06-18 /pmc/articles/PMC10112543/ /pubmed/35917738 http://dx.doi.org/10.1016/j.parkreldis.2022.06.010 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Loesch, Douglas P.
Horimoto, Andrea R.V.R.
Sarihan, Elif Irem
Inca-Martinez, Miguel
Mason, Emily
Cornejo-Olivas, Mario
Torres, Luis
Mazzetti, Pilar
Cosentino, Carlos
Sarapura-Castro, Elison
Rivera-Valdivia, Andrea
Medina, Angel C.
Dieguez, Elena
Raggio, Victor
Lescano, Andres
Tumas, Vitor
Borges, Vanderci
Ferraz, Henrique B.
Rieder, Carlos R.
Schumacher-Schuh, Artur
Santos-Lobato, Bruno L.
Velez-Pardo, Carlos
Jimenez-Del-Rio, Marlene
Lopera, Francisco
Moreno, Sonia
Chana-Cuevas, Pedro
Fernandez, William
Arboleda, Gonzalo
Arboleda, Humberto
Arboleda-Bustos, Carlos E.
Yearout, Dora
Zabetian, Cyrus P.
Thornton, Timothy A.
Mata, Ignacio F.
O’Connor, Timothy D.
Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson’s disease cohort
title Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson’s disease cohort
title_full Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson’s disease cohort
title_fullStr Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson’s disease cohort
title_full_unstemmed Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson’s disease cohort
title_short Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson’s disease cohort
title_sort polygenic risk prediction and snca haplotype analysis in a latino parkinson’s disease cohort
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10112543/
https://www.ncbi.nlm.nih.gov/pubmed/35917738
http://dx.doi.org/10.1016/j.parkreldis.2022.06.010
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