Alexandra I Soto-Beasley1, Ronald L Walton1, Rebecca R Valentino1, Paul W Hook2, Catherine Labbé1, Michael G Heckman3, Patrick W Johnson3, Loyal A Goff4, Ryan J Uitti5, Pamela J McLean6, Wolfdieter Springer6, Andrew S McCallion7, Zbigniew K Wszolek5, Owen A Ross8. 1. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA. 2. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 3. Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, 32224, USA. 4. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Solomon H. Snyder Department of Neuroscience and Kavli Neurodiscovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 5. Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA. 6. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA; Neuroscience PhD Program, Mayo Clinic Graduate School of Biomedical Sciences, USA. 7. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. 8. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, 32224, USA; School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Neuroscience PhD Program, Mayo Clinic Graduate School of Biomedical Sciences, USA; Department of Biology, College of Arts and Sciences, University of North Florida, Jacksonville, FL, 32224, USA. Electronic address: ross.owen@mayo.edu.
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.
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.
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