Proxy-analysis of the genetics of cognitive decline in Parkinson's disease through polygenic scores.

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Cognitive decline is common in Parkinson's disease (PD) and its genetic risk factors are not well known to date, besides variants in the GBA and APOE genes. However, variation in complex traits is caused by numerous variants and is usually studied with genome-wide association studies (GWAS), requiring a large sample size, which is difficult to achieve for outcome measures in PD. Taking an alternative approach, we computed 100 polygenic scores (PGS) related to cognitive, dementia, stroke, and brain anatomical phenotypes and investigated their association with cognitive decline in six longitudinal cohorts. The analysis was adjusted for age, sex, genetic ancestry, follow-up duration, GBA and APOE status. Then, we meta-analyzed five of these cohorts, comprising a total of 1702 PD participants with 6156 visits, using the Montreal Cognitive Assessment as a cognitive outcome measure. After correction for multiple comparisons, we found four PGS significantly associated with cognitive decline: intelligence (p = 5.26e-13), cognitive performance (p = 1.46e-12), educational attainment (p = 8.52e-10), and reasoning (p = 3.58e-5). Survival analyses highlighted an offset of several years between the first and last quartiles of PGS, with significant differences for the PGS of cognitive performance (5 years) and educational attainment (7 years). In conclusion, we found four PGS associated with cognitive decline in PD, all associated with general cognitive phenotypes. This study highlights the common genetic factors between cognitive decline in PD and the general population, and the importance of the participant's cognitive reserve for cognitive outcome in PD.

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