INTRODUCTION: Genome-wide association studies (GWAS) have confirmed the leucine-rich repeat kinase 2 (LRRK2) gene as a susceptibility locus for idiopathic Parkinson's disease (PD) in Caucasians. Though the rs1491942 and rs76904798 variants have shown the strongest associations, the causal variant(s) remains unresolved. Therefore, the aim of this study was to identify variants that may be driving the LRRK2 GWAS signal by sequencing the entire LRRK2 gene in Caucasian PD patients and controls. METHODS: A discovery series (287 PD patients, 294 controls) and replication series (362 PD patients, 168 controls) were included. The entire LRRK2 gene as well as 10 Kb upstream/downstream was sequenced. Candidate potential causal variants were considered to be those that (a) were in at least weak linkage disequilibrium with the two GWAS-nominated variants (rs1491942 and rs76904798), and (b) displayed an association odds ratio (OR) that is stronger than the two GWAS variants. RESULTS: Thirty-four candidate variants (all intronic/intergenic) that may drive the LRRK2 PD GWAS signal were identified in the discovery series. However, examination of the replication series for these variants did not reveal any with a consistently stronger OR than both PD GWAS variants. Evaluation of public databases to determine which candidate variants are most likely to have a direct functional effect on LRRK2 expression was inconclusive. CONCLUSION: Though our findings provide novel insights into the LRRK2 GWAS association, a clear causal variant was not identified. The identified candidate variants can form the basis for future experiments and functional studies that can more definitively assess causal LRRK2 variants.
INTRODUCTION: Genome-wide association studies (GWAS) have confirmed the leucine-rich repeat kinase 2 (LRRK2) gene as a susceptibility locus for idiopathic Parkinson's disease (PD) in Caucasians. Though the rs1491942 and rs76904798 variants have shown the strongest associations, the causal variant(s) remains unresolved. Therefore, the aim of this study was to identify variants that may be driving the LRRK2 GWAS signal by sequencing the entire LRRK2 gene in Caucasian PD patients and controls. METHODS: A discovery series (287 PD patients, 294 controls) and replication series (362 PD patients, 168 controls) were included. The entire LRRK2 gene as well as 10 Kb upstream/downstream was sequenced. Candidate potential causal variants were considered to be those that (a) were in at least weak linkage disequilibrium with the two GWAS-nominated variants (rs1491942 and rs76904798), and (b) displayed an association odds ratio (OR) that is stronger than the two GWAS variants. RESULTS: Thirty-four candidate variants (all intronic/intergenic) that may drive the LRRK2 PD GWAS signal were identified in the discovery series. However, examination of the replication series for these variants did not reveal any with a consistently stronger OR than both PD GWAS variants. Evaluation of public databases to determine which candidate variants are most likely to have a direct functional effect on LRRK2 expression was inconclusive. CONCLUSION: Though our findings provide novel insights into the LRRK2 GWAS association, a clear causal variant was not identified. The identified candidate variants can form the basis for future experiments and functional studies that can more definitively assess causal LRRK2 variants.
Authors: Daniel J Schaid; Charles M Rowland; David E Tines; Robert M Jacobson; Gregory A Poland Journal: Am J Hum Genet Date: 2001-12-27 Impact factor: 11.025
Authors: Alexandra I Soto-Ortolaza; Michael G Heckman; Catherine Labbé; Daniel J Serie; Andreas Puschmann; Sruti Rayaprolu; Audrey Strongosky; Magdalena Boczarska-Jedynak; Grzegorz Opala; Anna Krygowska-Wajs; Maria Barcikowska; Krzysztof Czyzewski; Timothy Lynch; Ryan J Uitti; Zbigniew K Wszolek; Owen A Ross Journal: Am J Neurodegener Dis Date: 2013-11-29
Authors: Michael A Nalls; Vincent Plagnol; Dena G Hernandez; Manu Sharma; Una-Marie Sheerin; Mohamad Saad; J Simón-Sánchez; Claudia Schulte; Suzanne Lesage; Sigurlaug Sveinbjörnsdóttir; Kári Stefánsson; Maria Martinez; John Hardy; Peter Heutink; Alexis Brice; Thomas Gasser; Andrew B Singleton; Nicholas W Wood Journal: Lancet Date: 2011-02-01 Impact factor: 79.321
Authors: Alan P Boyle; Eurie L Hong; Manoj Hariharan; Yong Cheng; Marc A Schaub; Maya Kasowski; Konrad J Karczewski; Julie Park; Benjamin C Hitz; Shuai Weng; J Michael Cherry; Michael Snyder Journal: Genome Res Date: 2012-09 Impact factor: 9.043
Authors: Cornelis Blauwendraat; Xylena Reed; Demis A Kia; Ziv Gan-Or; Suzanne Lesage; Lasse Pihlstrøm; Rita Guerreiro; J Raphael Gibbs; Marya Sabir; Sarah Ahmed; Jinhui Ding; Roy N Alcalay; Sharon Hassin-Baer; Alan M Pittman; Janet Brooks; Connor Edsall; Dena G Hernandez; Sun Ju Chung; Stefano Goldwurm; Mathias Toft; Claudia Schulte; Jose Bras; Nicholas W Wood; Alexis Brice; Huw R Morris; Sonja W Scholz; Mike A Nalls; Andrew B Singleton; Mark R Cookson Journal: JAMA Neurol Date: 2018-11-01 Impact factor: 18.302
Authors: Daniah Trabzuni; Mina Ryten; Warren Emmett; Adaikalavan Ramasamy; Karl J Lackner; Tanja Zeller; Robert Walker; Colin Smith; Patrick A Lewis; Adamantios Mamais; Rohan de Silva; Jana Vandrovcova; Dena Hernandez; Michael A Nalls; Manu Sharma; Sophie Garnier; Suzanne Lesage; Javier Simon-Sanchez; Thomas Gasser; Peter Heutink; Alexis Brice; Andrew Singleton; Huaibin Cai; Eric Schadt; Nicholas W Wood; Rina Bandopadhyay; Michael E Weale; John Hardy; Vincent Plagnol Journal: PLoS One Date: 2013-08-13 Impact factor: 3.240
Authors: Julie Lake; Xylena Reed; Rebekah G Langston; Mike A Nalls; Ziv Gan-Or; Mark R Cookson; Andrew B Singleton; Cornelis Blauwendraat; Hampton L Leonard Journal: Mov Disord Date: 2021-09-20 Impact factor: 9.698