Large-scale replication and heterogeneity in Parkinson disease genetic loci

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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
Organisations
External organisations
  • Skåne University Hospital
  • University of Tübingen
  • Antwerp University Hospital
  • National and Kapodistrian University of Athens
  • University of Antwerp
  • National Institute for Health and Medical Research, France
  • St. Olav’s University Hospital
  • Stanford University
  • German Center for Neurodegenerative Diseases (DZNE), Bonn
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics

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
Original languageEnglish
Pages (from-to)659-67
Number of pages9
JournalNeurology
Volume79
Issue number7
Publication statusPublished - 2012 Aug 14
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

Andreas Puschmann is part of Group Author