The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight

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The Genetic Architecture of Parkinson Disease in Spain : Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight. / American Genome Center.

In: Movement Disorders, Vol. 34, No. 12, 12.2019, p. 1851-1863.

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@article{1052357a9311458489b549a45567042e,
title = "The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight",
abstract = "BACKGROUND: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.OBJECTIVES: To perform the largest PD genome-wide association study restricted to a single country.METHODS: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses.RESULTS: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.CONCLUSIONS: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. {\textcopyright} 2019 International Parkinson and Movement Disorder Society.",
author = "{American Genome Center} and Sara Bandres-Ciga and Sarah Ahmed and Sabir, {Marya S} and Cornelis Blauwendraat and Adarmes-G{\'o}mez, {Astrid D} and Inmaculada Bernal-Bernal and Marta Bonilla-Toribio and Dolores Buiza-Rueda and F{\'a}tima Carrillo and Mario Carri{\'o}n-Claro and Pilar G{\'o}mez-Garre and Silvia Jes{\'u}s and Labrador-Espinosa, {Miguel A} and Daniel Macias and Carlota M{\'e}ndez-Del-Barrio and Teresa Peri{\~n}{\'a}n-Tocino and Cristina Tejera-Parrado and Laura Vargas-Gonz{\'a}lez and Monica Diez-Fairen and Ignacio Alvarez and Tartari, {Juan Pablo} and Mariateresa Buongiorno and Miquel Aguilar and Ana Gorostidi and Bergareche, {Jes{\'u}s Alberto} and Elisabet Mondragon and Ana Vinagre-Aragon and Ioana Croitoru and Javier Ruiz-Mart{\'i}nez and Oriol Dols-Icardo and Jaime Kulisevsky and Juan Mar{\'i}n-Lahoz and Javier Pagonabarraga and Berta Pascual-Sedano and Mario Ezquerra and Ana C{\'a}mara and Yaroslau Compta and Manel Fern{\'a}ndez and Rub{\'e}n Fern{\'a}ndez-Santiago and Esteban Mu{\~n}oz and Eduard Tolosa and Francesc Valldeoriola and Isabel Gonzalez-Aramburu and {Sanchez Rodriguez}, Antonio and Mar{\'i}a Sierra and Manuel Men{\'e}ndez-Gonz{\'a}lez and Marta Blazquez and Ciara Garcia and {Suarez-San Martin}, Esther and Carl Clarke",
note = "{\textcopyright} 2019 International Parkinson and Movement Disorder Society.",
year = "2019",
month = dec,
doi = "10.1002/mds.27864",
language = "English",
volume = "34",
pages = "1851--1863",
journal = "Movement Disorders",
issn = "0885-3185",
publisher = "Wiley",
number = "12",

}

RIS

TY - JOUR

T1 - The Genetic Architecture of Parkinson Disease in Spain

T2 - Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight

AU - American Genome Center

AU - Bandres-Ciga, Sara

AU - Ahmed, Sarah

AU - Sabir, Marya S

AU - Blauwendraat, Cornelis

AU - Adarmes-Gómez, Astrid D

AU - Bernal-Bernal, Inmaculada

AU - Bonilla-Toribio, Marta

AU - Buiza-Rueda, Dolores

AU - Carrillo, Fátima

AU - Carrión-Claro, Mario

AU - Gómez-Garre, Pilar

AU - Jesús, Silvia

AU - Labrador-Espinosa, Miguel A

AU - Macias, Daniel

AU - Méndez-Del-Barrio, Carlota

AU - Periñán-Tocino, Teresa

AU - Tejera-Parrado, Cristina

AU - Vargas-González, Laura

AU - Diez-Fairen, Monica

AU - Alvarez, Ignacio

AU - Tartari, Juan Pablo

AU - Buongiorno, Mariateresa

AU - Aguilar, Miquel

AU - Gorostidi, Ana

AU - Bergareche, Jesús Alberto

AU - Mondragon, Elisabet

AU - Vinagre-Aragon, Ana

AU - Croitoru, Ioana

AU - Ruiz-Martínez, Javier

AU - Dols-Icardo, Oriol

AU - Kulisevsky, Jaime

AU - Marín-Lahoz, Juan

AU - Pagonabarraga, Javier

AU - Pascual-Sedano, Berta

AU - Ezquerra, Mario

AU - Cámara, Ana

AU - Compta, Yaroslau

AU - Fernández, Manel

AU - Fernández-Santiago, Rubén

AU - Muñoz, Esteban

AU - Tolosa, Eduard

AU - Valldeoriola, Francesc

AU - Gonzalez-Aramburu, Isabel

AU - Sanchez Rodriguez, Antonio

AU - Sierra, María

AU - Menéndez-González, Manuel

AU - Blazquez, Marta

AU - Garcia, Ciara

AU - Suarez-San Martin, Esther

AU - Clarke, Carl

N1 - © 2019 International Parkinson and Movement Disorder Society.

PY - 2019/12

Y1 - 2019/12

N2 - BACKGROUND: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.OBJECTIVES: To perform the largest PD genome-wide association study restricted to a single country.METHODS: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses.RESULTS: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.CONCLUSIONS: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.

AB - BACKGROUND: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.OBJECTIVES: To perform the largest PD genome-wide association study restricted to a single country.METHODS: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses.RESULTS: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.CONCLUSIONS: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.

U2 - 10.1002/mds.27864

DO - 10.1002/mds.27864

M3 - Article

C2 - 31660654

VL - 34

SP - 1851

EP - 1863

JO - Movement Disorders

JF - Movement Disorders

SN - 0885-3185

IS - 12

ER -