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.
Keywords: GBA1; LRRK2; Parkinson's disease; alpha-synuclein; polygenic risk score.
Parkinson's disease (PD) is a genetically complex condition, caused by genetic and environmental risk factors. While specific mutations in the GBA1 and LRRK2 genes are major risk factors, most carriers will not develop PD. Here we examined why some carriers develop PD and others do not. Although environmental factors may influence this risk, we hypothesized that additional genetic risk factors play a role in disease development. Specifically, we tested if 86 known PD risk factors, analyzed as a polygenic risk score (PRS), increase PD risk in carriers, and affect disease phenotypes. This was tested in 715 unrelated individuals (PD patients and non-PD individuals), all of Ashkenazi Jewish ancestry. We split the cohort into 3 genetic groups: carriers of LRRK2 G2019S, carriers of risk variants in GBA1, and non-carriers (NC) of LRRK2 G2019S or GBA1 variants. Publicly available databases were used for validation. We found that elevated PRS (carrying many disease risk factors) was associated with increased PD risk in all three groups, but the effect was small. One risk factor (rs7938782-A) was significantly associated with PD risk in LRRK2 G2019S carriers but not in GBA1 carriers or NC, and its biological role should further be explored. Higher PRS was significantly associated with an earlier age-at-motor-symptoms-onset in NC. These findings indicates that PD risk across different genetic groups is affected by a combination of many changes in the genome. Future PRS models should be developed to better assess PD risk for different genetic backgrounds.