@article{81e5b73b877648f98085a037bc48eec5,
title = "Fine-mapping of the non-coding variation driving the Caucasian LRRK2 GWAS signal in Parkinson's disease",
abstract = "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.",
keywords = "Genetics, Genome-wide association study, LRRK2, Parkinson's disease, Sequencing",
author = "Heckman, {Michael G.} and Catherine Labb{\'e} and Kolicheski, {Ana L.} and Soto-Beasley, {Alexandra I.} and Walton, {Ronald L.} and Valentino, {Rebecca R.} and Brennan, {Emily R.} and Johnson, {Patrick W.} and Saurabh Baheti and Vivekananda Sarangi and Yingxue Ren and Uitti, {Ryan J.} and Wszolek, {Zbigniew K.} and Ross, {Owen A.}",
note = "Funding Information: We are grateful to all patients, family members, and caregivers who agreed to blood donation; without their donation these studies would have been impossible. We appreciate the assistance of Mayo Clinic Udall Center former administrator, Audrey Strongosky, C.C.R.C. This study was performed with support from the Michael J. Fox Foundation and Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, and the Mangurian Foundation for Lewy body research. Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research and the Mayo Clinic Lewy Body Dementia Association (LBDA) Research Center of Excellence. PPMI ? a public-private partnership ? is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including Abbvie, Allergan, Amathus Therapeutics, Avid Radiopharmaceuticals, Biogen, BioLegend, Bristol-Myers Squibb, Celgene, Denali, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Prevail, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily, and Voyager. The PPMI Investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to date information on the study, visit www.ppmi-info.org.OAR is supported by the National Institutes of Health (NIH; R01 NS78086; U54 NS100693; U54 NS110435), the US Department of Defense (W81XWH-17-1-0249), Mayo Clinic Center for Individualized Medicine, and The Functional Genomics of LBD Program at the Mayo Clinic. ZKW is partially supported by the Mayo Clinic Center for Regenerative Medicine, the gifts from The Sol Goldman Charitable Trust, and the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. He serves as MCF site PI on Biogen, Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301) grants. He serves as PI of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center. Funding Information: OAR is supported by the National Institutes of Health (NIH; R01 NS78086 ; U54 NS100693 ; U54 NS110435 ), the US Department of Defense (W81XWH-17-1-0249), Mayo Clinic Center for Individualized Medicine , and The Functional Genomics of LBD Program at the Mayo Clinic . ZKW is partially supported by the Mayo Clinic Center for Regenerative Medicine, the gifts from The Sol Goldman Charitable Trust , and the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation . He serves as MCF site PI on Biogen , Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301) grants. He serves as PI of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center. Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",
year = "2021",
month = feb,
doi = "10.1016/j.parkreldis.2020.12.016",
language = "English (US)",
volume = "83",
pages = "22--30",
journal = "Parkinsonism and Related Disorders",
issn = "1353-8020",
publisher = "Elsevier BV",
}