Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes

• Published in: bioRxiv
• Main Authors: Alfradique-Dunham, Isabel, Al-Ouran, Rami, Rainer Von Coelln, Blauwendraat, Cornelis, Hill, Emily, Luo, Lan, Stillwell, Amanda, Young, Emily, Tan, Manuela, Liao, Calwing, Hernandez, Dena, Pihlstrom, Lasse, Grosset, Donald, Shulman, Lisa M, Liu, Zhandong, Rouleau, Guy, International Parkinson's Disease Genomics Consortium, Nalls, Mike A, Singleton, Andrew, Morris, Huw, Jankovic, Joseph, Shulman, Joshua M
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 27.06.2020
• Subjects: Alleles; Gait; Genome-wide association studies; Genomes; Medical research; Movement disorders; Neurodegenerative diseases; Parkinson's disease; Parkinsons disease; Patent applications; Regression analysis; Tremor; Tremor (Muscular contraction)
• DOI: 10.1101/2020.06.26.174276

OBJECTIVE: To discover genetic determinants of Parkinson disease (PD) motor subtypes, including Tremor Dominant (TD) and Postural Instability/Gait Difficulty (PIGD) forms. METHODS: In 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining two complementary outcome traits derived from the Unified Parkinson Disease Rating Scale (UPDRS), including dichotomous motor subtype (TD vs. PIGD) or a continuous tremor / PIGD score ratio. Logistic or linear regression models were adjusted for sex, age of onset, disease duration, and 5 ancestry principal components, followed by meta-analysis. RESULTS: Among 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199347, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, Beta = 0.04, 95% CI = 0.07, 0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6x10-7), which harbors an independent risk allele for essential tremor. CONCLUSIONS: Multiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD. Competing Interest Statement I. Alfradique-Dunham, R. Al-Ouran, R. von Coelln, C. Blauwendraat, E. Hill, L. Luo, A. Stillwell, E. Young, M. Tan, C. Liao, L. Pihlstrom, J. Marinus, J.J. Van Hilten, D. Grosset, L. Shulman, Z. Liu, G. Rouleau, M. Nalls, A. Singleton, and J. Jankovic report no disclosures relevant to the manuscript. Dr. Nalls consults for Illumina Inc, Lysosomal Therapeutics Inc, the Michael J. Fox Foundation and Vivid Genomics among others. H Morris is employed by UCL and discloses paid consultancy from Biogen, UCB, Abbvie, Denali, Biohaven, Lundbeck; lecture fees/honoraria from Biogen, UCB, C4X Discovery, GE-Healthcare, Wellcome Trust, Movement Disorders Society; Dr Morris is a co-applicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). Dr. Grossett received honoraria from GE Healthcare, Bial Pharma, and Vectura plc, and consultancy fees from The Glasgow Memory Clinic. J. Shulman consults for the Adrienne Helis Malvin & Diana Helis Henry Medical Research Foundations.