Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease

Abstract

For Parkinson's disease (PD) the main driver of patients’ well-being and clinical trials is the course disease takes over time (progression and prognosis), not susceptibility. The pace of deterioration varies dramatically between patients for reasons that are poorly understood. Most previous genome-wide analyses were static and could not resolve the critical time dimension. To characterize how genetic variation influences the progression of PD over time to dementia, which is a major determinant for quality of life, we performed a longitudinal genome-wide survival study (GWSS). 11.2 million deeply imputed variants in 3,821 PD patients who were prospectively tracked with 36,123 visits over a median of 6.7 years from disease onset (inter-quartile range, 4.2 years) were analyzed. Progression to dementia and decline in Mini Mental State Exam scores was determined using cox proportional hazards and mixed random and fixed effects models. The Regulating Synaptic Membrane Exocytosis 2 (RIMS2) locus achieved genome-wide significance in the discovery population and was validated in the replication population. The RIMS2 variant conferred a hazard ratio (HR) of 4.77 (95% confidence interval (CI) 3.01 – 7.56) with P = 2.78 × 10-11. Two other loci reached meta-analysis P values <5 x 10-8. None of these had been associated with susceptibility for PD. Risk profile analysis with a polygenic hazard score revealed a substantial aggregate association with dementia risk. This was augmented by GBA and APOE, while the polygenic effect of susceptibility loci was not predictive. This study uncovers variants associated with prognosis that differ from susceptibility-linked variants. It provides a versatile enrichment score for clinical trials and suggests divergence in the genetic architectures of disease onset and progression.