X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease

Thiago P. Leal; Shilpa C. Rao; Jennifer N. French-Kwawu; Mateus H. Gouveia; Victor Borda; Sara Bandres-Ciga; Miguel Inca-Martinez; Emily A. Mason; Andrea R.V.R. Horimoto; Douglas P. Loesch; Elif I. Sarihan; Mario R. Cornejo-Olivas; Luis E. Torres; Pilar E. Mazzetti-Soler; Carlos Cosentino; Elison H. Sarapura-Castro; Andrea Rivera-Valdivia; Angel C. Medina; Elena M. Dieguez; Víctor E. Raggio; Andrés Lescano; Vitor Tumas; Vanderci Borges; Henrique B. Ferraz; Carlos R. Rieder; Artur Schumacher Schuh; Bruno L. Santos-Lobato; Carlos Velez-Pardo; Marlene Jimenez-Del-Rio; Francisco Lopera; Sonia Moreno; Pedro Chana-Cuevas; William Fernandez; Gonzalo Arboleda; Humberto Arboleda; Carlos E. Arboleda Bustos; Dora Yearout; Maira T. Barbosa; Francisco E.C. Cardoso; Paulo Caramelli; Mauro C.Q. Cunningham; Débora P. Maia; Maria F. Lima-Costa; Eduardo Tarazona-Santos; Cyrus P. Zabetian; Timothy A. Thornton; Timothy D. O'Connor; Ignacio F. Mata

doi:10.1002/mds.29508

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease

Thiago P. Leal, Shilpa C. Rao, Jennifer N. French-Kwawu, Mateus H. Gouveia, Victor Borda, Sara Bandres-Ciga, Miguel Inca-Martinez, Emily A. Mason, Andrea R.V.R. Horimoto, Douglas P. Loesch, Elif I. Sarihan, Mario R. Cornejo-Olivas, Luis E. Torres, Pilar E. Mazzetti-Soler, Carlos Cosentino, Elison H. Sarapura-Castro, Andrea Rivera-Valdivia, Angel C. Medina, Elena M. Dieguez, Víctor E. RaggioAndrés Lescano, Vitor Tumas, Vanderci Borges, Henrique B. Ferraz, Carlos R. Rieder, Artur Schumacher Schuh, Bruno L. Santos-Lobato, Carlos Velez-Pardo, Marlene Jimenez-Del-Rio, Francisco Lopera, Sonia Moreno, Pedro Chana-Cuevas, William Fernandez, Gonzalo Arboleda, Humberto Arboleda, Carlos E. Arboleda Bustos, Dora Yearout, Maira T. Barbosa, Francisco E.C. Cardoso, Paulo Caramelli, Mauro C.Q. Cunningham, Débora P. Maia, Maria F. Lima-Costa, Eduardo Tarazona-Santos, Cyrus P. Zabetian, Timothy A. Thornton, Timothy D. O'Connor, Ignacio F. Mata

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Abstract

Background: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. Objective: The objective of this study was to perform the first X-chromosome–wide association study for PD risk in a Latin American cohort. Methods: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. Results: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478–0.77], P = 3.13 × 10⁻⁵ replication odds ratio: 0.60 [0.37–0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome–wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. Conclusions: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies.

Original language	English
Pages (from-to)	1625-1635
Number of pages	11
Journal	Movement Disorders
Volume	38
Issue number	9
DOIs	https://doi.org/10.1002/mds.29508
State	Published - Sep 2023

Keywords

Parkinson's disease
admixed populations
hipanic/latino
underrepresented populations
x-chromosome wide association study

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10.1002/mds.29508

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Leal, T. P., Rao, S. C., French-Kwawu, J. N., Gouveia, M. H., Borda, V., Bandres-Ciga, S., Inca-Martinez, M., Mason, E. A., Horimoto, A. R. V. R., Loesch, D. P., Sarihan, E. I., Cornejo-Olivas, M. R., Torres, L. E., Mazzetti-Soler, P. E., Cosentino, C., Sarapura-Castro, E. H., Rivera-Valdivia, A., Medina, A. C., Dieguez, E. M., ... Mata, I. F. (2023). X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease. Movement Disorders, 38(9), 1625-1635. https://doi.org/10.1002/mds.29508

@article{7093917ce37f46a4a267985f4e5a40ab,

title = "X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease",

abstract = "Background: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. Objective: The objective of this study was to perform the first X-chromosome–wide association study for PD risk in a Latin American cohort. Methods: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. Results: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478–0.77], P = 3.13 × 10−5 replication odds ratio: 0.60 [0.37–0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome–wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. Conclusions: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies.",

keywords = "Parkinson's disease, admixed populations, hipanic/latino, underrepresented populations, x-chromosome wide association study",

author = "Leal, {Thiago P.} and Rao, {Shilpa C.} and French-Kwawu, {Jennifer N.} and Gouveia, {Mateus H.} and Victor Borda and Sara Bandres-Ciga and Miguel Inca-Martinez and Mason, {Emily A.} and Horimoto, {Andrea R.V.R.} and Loesch, {Douglas P.} and Sarihan, {Elif I.} and Cornejo-Olivas, {Mario R.} and Torres, {Luis E.} and Mazzetti-Soler, {Pilar E.} and Carlos Cosentino and Sarapura-Castro, {Elison H.} and Andrea Rivera-Valdivia and Medina, {Angel C.} and Dieguez, {Elena M.} and Raggio, {V{\'i}ctor E.} and Andr{\'e}s Lescano and Vitor Tumas and Vanderci Borges and Ferraz, {Henrique B.} and Rieder, {Carlos R.} and {Schumacher Schuh}, Artur and Santos-Lobato, {Bruno L.} and Carlos Velez-Pardo and Marlene Jimenez-Del-Rio and Francisco Lopera and Sonia Moreno and Pedro Chana-Cuevas and William Fernandez and Gonzalo Arboleda and Humberto Arboleda and {Arboleda Bustos}, {Carlos E.} and Dora Yearout and Barbosa, {Maira T.} and Cardoso, {Francisco E.C.} and Paulo Caramelli and Cunningham, {Mauro C.Q.} and Maia, {D{\'e}bora P.} and Lima-Costa, {Maria F.} and Eduardo Tarazona-Santos and Zabetian, {Cyrus P.} and Thornton, {Timothy A.} and O'Connor, {Timothy D.} and Mata, {Ignacio F.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",

year = "2023",

month = sep,

doi = "10.1002/mds.29508",

language = "Ingl{\'e}s",

volume = "38",

pages = "1625--1635",

journal = "Movement Disorders",

issn = "0885-3185",

publisher = "John Wiley & Sons Inc.",

number = "9",

}

Leal, TP, Rao, SC, French-Kwawu, JN, Gouveia, MH, Borda, V, Bandres-Ciga, S, Inca-Martinez, M, Mason, EA, Horimoto, ARVR, Loesch, DP, Sarihan, EI, Cornejo-Olivas, MR, Torres, LE, Mazzetti-Soler, PE, Cosentino, C, Sarapura-Castro, EH, Rivera-Valdivia, A, Medina, AC, Dieguez, EM, Raggio, VE, Lescano, A, Tumas, V, Borges, V, Ferraz, HB, Rieder, CR, Schumacher Schuh, A, Santos-Lobato, BL, Velez-Pardo, C, Jimenez-Del-Rio, M, Lopera, F, Moreno, S, Chana-Cuevas, P, Fernandez, W, Arboleda, G, Arboleda, H, Arboleda Bustos, CE, Yearout, D, Barbosa, MT, Cardoso, FEC, Caramelli, P, Cunningham, MCQ, Maia, DP, Lima-Costa, MF, Tarazona-Santos, E, Zabetian, CP, Thornton, TA, O'Connor, TD & Mata, IF 2023, 'X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease', Movement Disorders, vol. 38, no. 9, pp. 1625-1635. https://doi.org/10.1002/mds.29508

TY - JOUR

T1 - X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease

AU - Leal, Thiago P.

AU - Rao, Shilpa C.

AU - French-Kwawu, Jennifer N.

AU - Gouveia, Mateus H.

AU - Borda, Victor

AU - Bandres-Ciga, Sara

AU - Inca-Martinez, Miguel

AU - Mason, Emily A.

AU - Horimoto, Andrea R.V.R.

AU - Loesch, Douglas P.

AU - Sarihan, Elif I.

AU - Cornejo-Olivas, Mario R.

AU - Torres, Luis E.

AU - Mazzetti-Soler, Pilar E.

AU - Cosentino, Carlos

AU - Sarapura-Castro, Elison H.

AU - Rivera-Valdivia, Andrea

AU - Medina, Angel C.

AU - Dieguez, Elena M.

AU - Raggio, Víctor E.

AU - Lescano, Andrés

AU - Tumas, Vitor

AU - Borges, Vanderci

AU - Ferraz, Henrique B.

AU - Rieder, Carlos R.

AU - Schumacher Schuh, Artur

AU - Santos-Lobato, Bruno L.

AU - Velez-Pardo, Carlos

AU - Jimenez-Del-Rio, Marlene

AU - Lopera, Francisco

AU - Moreno, Sonia

AU - Chana-Cuevas, Pedro

AU - Fernandez, William

AU - Arboleda, Gonzalo

AU - Arboleda, Humberto

AU - Arboleda Bustos, Carlos E.

AU - Yearout, Dora

AU - Barbosa, Maira T.

AU - Cardoso, Francisco E.C.

AU - Caramelli, Paulo

AU - Cunningham, Mauro C.Q.

AU - Maia, Débora P.

AU - Lima-Costa, Maria F.

AU - Tarazona-Santos, Eduardo

AU - Zabetian, Cyrus P.

AU - Thornton, Timothy A.

AU - O'Connor, Timothy D.

AU - Mata, Ignacio F.

PY - 2023/9

Y1 - 2023/9

N2 - Background: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. Objective: The objective of this study was to perform the first X-chromosome–wide association study for PD risk in a Latin American cohort. Methods: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. Results: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478–0.77], P = 3.13 × 10−5 replication odds ratio: 0.60 [0.37–0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome–wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. Conclusions: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies.

AB - Background: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. Objective: The objective of this study was to perform the first X-chromosome–wide association study for PD risk in a Latin American cohort. Methods: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. Results: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478–0.77], P = 3.13 × 10−5 replication odds ratio: 0.60 [0.37–0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome–wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. Conclusions: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies.

KW - Parkinson's disease

KW - admixed populations

KW - hipanic/latino

KW - underrepresented populations

KW - x-chromosome wide association study

UR - http://www.scopus.com/inward/record.url?scp=85165612886&partnerID=8YFLogxK

U2 - 10.1002/mds.29508

DO - 10.1002/mds.29508

M3 - Artículo

C2 - 37469269

AN - SCOPUS:85165612886

SN - 0885-3185

VL - 38

SP - 1625

EP - 1635

JO - Movement Disorders

JF - Movement Disorders

IS - 9

ER -

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease

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Keywords

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