@article{899e9df6d3334a9985377cb1647456ba,
title = "Screening non-MAPT genes of the Chr17q21 H1 haplotype in Parkinson's disease",
abstract = "Introduction: The microtubule-associated protein tau (MAPT) gene is considered a strong genetic risk factor for Parkinson's disease (PD) in Caucasians. MAPT is located within an inversion region of high linkage disequilibrium designated as H1 and H2 haplotype, and contains eight other genes which have been implicated in neurodegeneration. The aim of the current study was to identify common coding variants in strong linkage disequilibrium (LD) within the associated loci on chr17q21 harboring MAPT. Methods: Sanger sequencing of coding exons in 90 Caucasian late-onset PD (LOPD) patients was performed. Specific gene sequencing for LRRC37A, LRRC37A2, ARL17A and ARL17B was not possible given the high homology, presence of pseudogenes and copy number variants that are in the region, and therefore four genes (NSF, KANSL1, SPPL2C, and CRHR1) were included in the analysis. Coding variants from these four genes that did not perfectly tag (r2 = 1) the MAPT H1/H2 haplotype were genotyped in an independent replication series of Caucasian PD cases (N = 851) and controls (N = 730). Results: In the 90 LOPD cases we identified 30 coding variants. Eleven non-synonymous variants tagged the MAPT H1/H2 haplotype, including two SPPL2C variants (rs12185233 and rs12373123) that had high pathogenic combined annotation dependent depletion (CADD) scores of >20. In the replication series, the non-synonymous KANSL1 rs17585974 variant was in very strong LD with MAPT H1/H2 and had a high CADD score of 24.7. Conclusion: We have identified several non-synonymous variants across neighboring genes of MAPT that may warrant further genetic and functional investigation within the biological etiology of PD.",
keywords = "CRHR1, H1 haplotype, KANSL1, MAPT, NSF, Parkinson's disease, SPPL2C",
author = "Soto-Beasley, {Alexandra I.} and Walton, {Ronald L.} and Valentino, {Rebecca R.} and Hook, {Paul W.} and Catherine Labb{\'e} and Heckman, {Michael G.} and Johnson, {Patrick W.} and Goff, {Loyal A.} and Uitti, {Ryan J.} and McLean, {Pamela J.} and Wolfdieter Springer and McCallion, {Andrew S.} and Wszolek, {Zbigniew K.} and Ross, {Owen A.}",
note = "Funding Information: Owen A. Ross received support from R01-NS078086, P50-NS072187, U54 NS100693, U54 NS110435, the US Department of Defense (W81XWH-17-1-0249), the Mayo Clinic LBD Functional Genomics Program, The Littlegdation, and the Michael J. Fox Foundation. Funding Information: Zbigniew K. Wszolek is partially supported by the Mayo Clinic Center for Regenerative Medicine, the gifts from The Sol Goldman Charitable Trust, Albertson Parkinson's Research Foundation and the Donald G. and Jodi P. Heeringa Family, and by the Haworth Family Professorship in Neurodegenerative Diseases fund. He serves as PI or Co-PI on Biogen, Inc. (228PD201) and Biohaven Pharmaceuticals, Inc (BHV4157-206, BHV3241-301) grants. He serves as PI of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as Co-PI of the Mayo Clinic APDA Center for Advanced Research. Funding Information: Zbigniew K. Wszolek recruited patients from the clinic to participate in this study, maintained IRB approvals and provided administrative and financial support. Funding Information: The authors would like to thank all those who have contributed to our research, particularly the patients and families who donated DNA samples, and our clinical coordinators Audrey Strongosky and Anne Martin. The Mayo Clinic is an American Parkinson Disease Association (APDA) Information and Referral Center, an APDA Center for Advanced Research, a Lewy Body Dementia Association Research Center of Excellence and was a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 NS072187). CL was the recipient of a FRSQ postdoctoral fellowship and was a 2015 Younkin Scholar supported by the Mayo Clinic Alzheimer's Disease and Related Dementias Genetics program. ASM and PWH were supported in part by awards from NIH (NS62972 and MH106522) and by HELIS, Helis Medical Research Foundation to ASM. PJM is supported by Mayo Foundation for Medical Research, NIH; R01 NS110085, U54 NS110435 Lewy Body Dementia Center without Walls, APDA Mayo Clinic Center for Advanced Research, and an Ed and Ethel Moore Award from Florida department of Public Health. WS is partially supported by NIH [R01/RF1 NS085070, R01 NS110085, U54 NS110435 and R56 AG062556], the Department of Defense Congressionally Directed Medical Research Programs (CDMRP) [W81XWH-17-1-0248], the Florida Department of Health - Ed and Ethel Moore Alzheimer's Disease Research Program [9AZ10], the Michael J. Fox Foundation for Parkinson's Research (MJFF), the APDA, and the Mayo Clinic Center for Biomedical Discovery (CBD).OAR is supported by the National Institutes of Health (NIH; R01 NS78086; U54 NS100693), the US Department of Defense (W81XWH-17-1-0249), Lewy Body Dementia Center WithOut Walls U54 NS110435, The Michael J. Fox Foundation, the Mayo Clinic LBD Functional Genomics Program and The Little Family Foundation. Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd",
year = "2020",
month = sep,
doi = "10.1016/j.parkreldis.2020.07.022",
language = "English (US)",
volume = "78",
pages = "138--144",
journal = "Parkinsonism and Related Disorders",
issn = "1353-8020",
publisher = "Elsevier BV",
}