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

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 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at 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 (rs199351, p subtype = 0.01, p ratio = 0.03), SH3GL2 (rs10756907, p subtype = 0.02, p ratio = 0.01), HIP1R (rs10847864, p subtype = 0.02), RIT2 (rs12456492, p subtype = 0.02), and FBRSL1 (rs11610045, p subtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = -0.04, 95% confidence interval = -0.07-0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, p ratio = 6.6 × 10-7), 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.

Quantitative mobility measures complement the MDS-UPDRS for characterization of Parkinson's disease heterogeneity.

INTRODUCTION: Emerging technologies show promise for enhanced characterization of Parkinson's Disease (PD) motor manifestations. We evaluated quantitative mobility measures from a wearable device compared to the conventional motor assessment, the Movement Disorders Society-Unified PD Rating Scale part III (motor MDS-UPDRS). METHODS: We evaluated 176 PD subjects (mean age 65, 65% male, 66% H&Y stage 2) during routine clinic visits using the motor MDS-UPDRS and a 10-min motor protocol with a body-fixed sensor (DynaPort MT, McRoberts BV), including the 32-ft walk, Timed Up and Go (TUG), and standing posture with eyes closed. Regression models examined 12 quantitative mobility measures for associations with (i) motor MDS-UPDRS, (ii) motor subtype (tremor dominant vs. postural instability/gait difficulty), (iii) Montreal Cognitive Assessment (MoCA), and (iv) physical functioning disability (PROMIS-29). All analyses included age, gender, and disease duration as covariates. Models iii-iv were secondarily adjusted for motor MDS-UPDRS. RESULTS: Quantitative mobility measures from gait, TUG transitions, turning, and posture were significantly associated with motor MDS-UPDRS (7 of 12 measures, p < 0.05) and motor subtype (6 of 12 measures, p < 0.05). Compared with motor MDS-UPDRS, several quantitative mobility measures accounted for a 1.5- or 1.9-fold increased variance in either cognition or physical functioning disability, respectively. Among minimally-impaired subjects in the bottom quartile of motor MDS-UPDRS, including subjects with normal gait exam, the measures captured substantial residual motor heterogeneity. CONCLUSION: Clinic-based quantitative mobility assessments using a wearable sensor captured features of motor performance beyond those obtained with the motor MDS-UPDRS and may offer enhanced characterization of disease heterogeneity.

Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease.

OBJECTIVE: To determine how single nucleotide variants (SNVs) and copy number variants (CNVs) contribute to molecular diagnosis in familial Parkinson disease (PD), we integrated exome sequencing (ES) and genome-wide array-based comparative genomic hybridization (aCGH) and further probed CNV structure to reveal mutational mechanisms. METHODS: We performed ES on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated ES and aCGH data for pathogenic SNVs and CNVs at Mendelian PD gene loci. We confirmed SNVs via Sanger sequencing and further characterized CNVs with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing. RESULTS: Using ES, we discovered individuals with known pathogenic SNVs in GBA (p.Glu365Lys, p.Thr408Met, p.Asn409Ser, and p.Leu483Pro) and LRRK2 (p.Arg1441Gly and p.Gly2019Ser). Two subjects were each double heterozygotes for variants in GBA and LRRK2. Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.Asn52Metfs*29, p.Thr240Met, p.Pro437Leu, and p.Trp453*) and likely disrupting CNVs at the PRKN locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors. CONCLUSIONS: Integrated ES and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PRKN CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.