The effect of polygenic risk score on PD risk and phenotype in LRRK2 G2019S and GBA1 carriers

BackgroundWhile LRRK2 and GBA1 variants are associated with Parkinson's disease (PD), most carriers will not develop the disease.ObjectiveTo test if polygenic risk score (PRS) modifies disease risk and phenotypes in LRRK2 G2019S carriers, GBA1 carriers, and non-carriers (NC).MethodsWe genotyped 786 participants using Illumina's NeuroBooster-array (NBA) and sequenced the genome of 244, all of Ashkenazi ancestry (AJ), and calculated PRS to test its effects on clinically- and biologically-defined disease risk and phenotypes (n = 715). Among LRRK2 G2019S PD, we tested PRS association with α-synuclein seed-amplification-assay (n = 11). We used the PPMI and AMP-PD databases as validation cohorts.ResultsIn clinically-defined PD, PRS significantly modified disease risk in GBA1 carriers and in NC (p = 0.033 and p < 0.0001, respectively), and demonstrated a trend in LRRK2 G2019S carriers (p = 0.054), with similar effect sizes (OR = 1.55, 1.62, and 1.49, respectively). PRS association with PD risk in LRRK2 was primarily driven by the rs7938782-A risk allele, replicated in AMP-PD (268 AJs LRRK2 G2019S carriers). PRS and age-at-onset were negatively correlated in NC (p < 0.0001). NBA GBA1 genotype calls failed at GBA1 L483P and c.115 + 1G > A mutations. False negative call rate of 10.2% was observed for the imputed GBA1 N409S carriers.ConclusionsPRS contributes to PD risk across different genotypes. The genetic and epigenetic role of rs7938782 in LRRK2 PD risk should be further explored. Future PRS models should be tailored to specific genotypes to better understand penetrance and phenotypes. Furthermore, models predicting PD defined biologically rather than clinically may further identify genetic risk factors for synucleinopathies.