Large-scale replication and heterogeneity in Parkinson disease genetic loci

Manu Sharma; John P A Ioannidis; Jan O. Aasly; Grazia Annesi; Alexis Brice; Christine Van Broeckhoven; Lars Bertram; Maria Bozi; David Crosiers; Carl E Clarke; Maurizio Facheris; Matthew Farrer; Gaetan Garraux; Suzana Gispert; Georg Auburger; Carles Vilariño-Güell; Georgios M. Hadjigeorgiou; Andrew A Hicks; Nobutaka Hattori; Beom S. Jeon; Suzanne Lesage; Christina M. Lill; Juei-Jueng Lin; Timothy Lynch; Peter Lichtner; Anthony E Lang; Vincent Mok; Barbara Jasinska-Myga; George D. Mellick; Karen E. Morrison; Grzegorz Opala; Peter P Pramstaller; Irene Pichler; Sung-Sup Park; Aldo Quattrone; Ekaterina Rogaeva; Owen A. Ross; Leonidas Stefanis; Joanne D Stockton; Wataru Satake; Peter A. Silburn; Jessie Theuns; Eng-King Tan; Tatsushi Toda; Hiroyuki Tomiyama; Ryan J. Uitti; Karin Wirdefeldt; Zbigniew K Wszolek; Georgia Xiromerisiou; GEO-PD Consortium

doi:10.1212/WNL.0b013e318264e353

Large-scale replication and heterogeneity in Parkinson disease genetic loci

Manu Sharma, John P A Ioannidis, Jan O. Aasly, Grazia Annesi, Alexis Brice, Christine Van Broeckhoven, Lars Bertram, Maria Bozi, David Crosiers, Carl E Clarke, Maurizio Facheris, Matthew Farrer, Gaetan Garraux, Suzana Gispert, Georg Auburger, Carles Vilariño-Güell, Georgios M. Hadjigeorgiou, Andrew A Hicks, Nobutaka Hattori, Beom S. JeonSuzanne Lesage, Christina M. Lill, Juei-Jueng Lin, Timothy Lynch, Peter Lichtner, Anthony E Lang, Vincent Mok, Barbara Jasinska-Myga, George D. Mellick, Karen E. Morrison, Grzegorz Opala, Peter P Pramstaller, Irene Pichler, Sung-Sup Park, Aldo Quattrone, Ekaterina Rogaeva, Owen A. Ross, Leonidas Stefanis, Joanne D Stockton, Wataru Satake, Peter A. Silburn, Jessie Theuns, Eng-King Tan, Tatsushi Toda, Hiroyuki Tomiyama, Ryan J. Uitti, Karin Wirdefeldt, Zbigniew K Wszolek, Georgia Xiromerisiou, GEO-PD Consortium

Research output: Contribution to journal › Article › peer-review

Abstract

OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.

METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.

RESULTS: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.

CONCLUSION: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

Original language	English
Pages (from-to)	659-67
Number of pages	9
Journal	Neurology
Volume	79
Issue number	7
DOIs	https://doi.org/10.1212/WNL.0b013e318264e353
Publication status	Published - 2012 Aug 14

Bibliographical note

Andreas Puschmann is part of Group Author

Subject classification (UKÄ)

Medical Genetics

Free keywords

Aged
Alleles
Case-Control Studies
Female
Gene Frequency
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Male
Middle Aged
Parkinson Disease
Polymorphism, Single Nucleotide
Journal Article

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10.1212/WNL.0b013e318264e353

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414661/

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Sharma, M., Ioannidis, J. P. A., Aasly, J. O., Annesi, G., Brice, A., Van Broeckhoven, C., Bertram, L., Bozi, M., Crosiers, D., Clarke, C. E., Facheris, M., Farrer, M., Garraux, G., Gispert, S., Auburger, G., Vilariño-Güell, C., Hadjigeorgiou, G. M., Hicks, A. A., Hattori, N., ... GEO-PD Consortium (2012). Large-scale replication and heterogeneity in Parkinson disease genetic loci. Neurology, 79(7), 659-67. https://doi.org/10.1212/WNL.0b013e318264e353

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title = "Large-scale replication and heterogeneity in Parkinson disease genetic loci",

abstract = "OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.RESULTS: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.CONCLUSION: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.",

keywords = "Aged, Alleles, Case-Control Studies, Female, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Parkinson Disease, Polymorphism, Single Nucleotide, Journal Article",

author = "Manu Sharma and Ioannidis, {John P A} and Aasly, {Jan O.} and Grazia Annesi and Alexis Brice and {Van Broeckhoven}, Christine and Lars Bertram and Maria Bozi and David Crosiers and Clarke, {Carl E} and Maurizio Facheris and Matthew Farrer and Gaetan Garraux and Suzana Gispert and Georg Auburger and Carles Vilari{\~n}o-G{\"u}ell and Hadjigeorgiou, {Georgios M.} and Hicks, {Andrew A} and Nobutaka Hattori and Jeon, {Beom S.} and Suzanne Lesage and Lill, {Christina M.} and Juei-Jueng Lin and Timothy Lynch and Peter Lichtner and Lang, {Anthony E} and Vincent Mok and Barbara Jasinska-Myga and Mellick, {George D.} and Morrison, {Karen E.} and Grzegorz Opala and Pramstaller, {Peter P} and Irene Pichler and Sung-Sup Park and Aldo Quattrone and Ekaterina Rogaeva and Ross, {Owen A.} and Leonidas Stefanis and Stockton, {Joanne D} and Wataru Satake and Silburn, {Peter A.} and Jessie Theuns and Eng-King Tan and Tatsushi Toda and Hiroyuki Tomiyama and Uitti, {Ryan J.} and Karin Wirdefeldt and Wszolek, {Zbigniew K} and Georgia Xiromerisiou and {GEO-PD Consortium} and Andreas Puschmann",

note = "Andreas Puschmann is part of Group Author",

year = "2012",

month = aug,

day = "14",

doi = "10.1212/WNL.0b013e318264e353",

language = "English",

volume = "79",

pages = "659--67",

journal = "Neurology",

issn = "1526-632X",

publisher = "Lippincott Williams & Wilkins",

number = "7",

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Sharma, M, Ioannidis, JPA, Aasly, JO, Annesi, G, Brice, A, Van Broeckhoven, C, Bertram, L, Bozi, M, Crosiers, D, Clarke, CE, Facheris, M, Farrer, M, Garraux, G, Gispert, S, Auburger, G, Vilariño-Güell, C, Hadjigeorgiou, GM, Hicks, AA, Hattori, N, Jeon, BS, Lesage, S, Lill, CM, Lin, J-J, Lynch, T, Lichtner, P, Lang, AE, Mok, V, Jasinska-Myga, B, Mellick, GD, Morrison, KE, Opala, G, Pramstaller, PP, Pichler, I, Park, S-S, Quattrone, A, Rogaeva, E, Ross, OA, Stefanis, L, Stockton, JD, Satake, W, Silburn, PA, Theuns, J, Tan, E-K, Toda, T, Tomiyama, H, Uitti, RJ, Wirdefeldt, K, Wszolek, ZK, Xiromerisiou, G & GEO-PD Consortium 2012, 'Large-scale replication and heterogeneity in Parkinson disease genetic loci', Neurology, vol. 79, no. 7, pp. 659-67. https://doi.org/10.1212/WNL.0b013e318264e353

TY - JOUR

T1 - Large-scale replication and heterogeneity in Parkinson disease genetic loci

AU - Sharma, Manu

AU - Ioannidis, John P A

AU - Aasly, Jan O.

AU - Annesi, Grazia

AU - Brice, Alexis

AU - Van Broeckhoven, Christine

AU - Bertram, Lars

AU - Bozi, Maria

AU - Crosiers, David

AU - Clarke, Carl E

AU - Facheris, Maurizio

AU - Farrer, Matthew

AU - Garraux, Gaetan

AU - Gispert, Suzana

AU - Auburger, Georg

AU - Vilariño-Güell, Carles

AU - Hadjigeorgiou, Georgios M.

AU - Hicks, Andrew A

AU - Hattori, Nobutaka

AU - Jeon, Beom S.

AU - Lesage, Suzanne

AU - Lill, Christina M.

AU - Lin, Juei-Jueng

AU - Lynch, Timothy

AU - Lichtner, Peter

AU - Lang, Anthony E

AU - Mok, Vincent

AU - Jasinska-Myga, Barbara

AU - Mellick, George D.

AU - Morrison, Karen E.

AU - Opala, Grzegorz

AU - Pramstaller, Peter P

AU - Pichler, Irene

AU - Park, Sung-Sup

AU - Quattrone, Aldo

AU - Rogaeva, Ekaterina

AU - Ross, Owen A.

AU - Stefanis, Leonidas

AU - Stockton, Joanne D

AU - Satake, Wataru

AU - Silburn, Peter A.

AU - Theuns, Jessie

AU - Tan, Eng-King

AU - Toda, Tatsushi

AU - Tomiyama, Hiroyuki

AU - Uitti, Ryan J.

AU - Wirdefeldt, Karin

AU - Wszolek, Zbigniew K

AU - Xiromerisiou, Georgia

AU - GEO-PD Consortium

AU - Puschmann, Andreas

N1 - Andreas Puschmann is part of Group Author

PY - 2012/8/14

Y1 - 2012/8/14

N2 - OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.RESULTS: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.CONCLUSION: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

AB - OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.RESULTS: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.CONCLUSION: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

KW - Aged

KW - Alleles

KW - Case-Control Studies

KW - Female

KW - Gene Frequency

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Male

KW - Middle Aged

KW - Parkinson Disease

KW - Polymorphism, Single Nucleotide

KW - Journal Article

U2 - 10.1212/WNL.0b013e318264e353

DO - 10.1212/WNL.0b013e318264e353

M3 - Article

C2 - 22786590

SN - 1526-632X

VL - 79

SP - 659

EP - 667

JO - Neurology

JF - Neurology

IS - 7

ER -

Large-scale replication and heterogeneity in Parkinson disease genetic loci

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

Access to Document

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Cite this