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The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available. Methods: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership-Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses. Results: A higher polygenic resilience score was associated with a lower risk for PD (β = À0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h 2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci. Interpretation: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD.

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Background The influence of ethnicity and socioeconomic status on dementia risk, and the extent to which this is mediated by known risk factors remain incompletely understood. We addressed this issue using health records data from the diverse and deprived population of East London (<50% White and >50% in the most deprived quintile of the UK). Method We performed a nested case‐control study in over 1,000,000 East London inhabitants. We identified 4137 cases of all cause dementia, and matched on age and gender to controls with ratio 1:4. Logistic regression was used to calculated odds ratios (ORs) for exposures of ethnicity and UK Index of Multiple Deprivation (IMD), before and after inclusion in the model of established modifiable risk factors (type II diabetes, hypertension, smoking, body mass index, depression and hearing loss). In order to reflect the relative importance of known modifiable risk factors in this deprived multiracial population, we calculated weighted population attributable fractions (PAF) for each factor. Result Risk of dementia was higher in the Black and South Asian groups relative to White (ORs (95%CI) Black 1.43 (1.31, 1.56), South Asian 1.17 (1.06, 1.29)). Risk of dementia was reduced in all IMD quintiles relative to the most deprived (ORs (95%CI) 2nd 0.71 (0.66, 0.77), 3rd 0.52 (0.44, 0.60), 4th 0.71 (0.53, 0.94), 5th 0.59 (0.38, 0.87)). The effects of ethnicity and deprivation persisted after adjusting for known risk factors. Weighted PAFs for modifiable risk factors were notably higher in this population for depression (9.2%) and diabetes (6.2%) than those estimated in the Lancet Commission meta‐analyses (4% and 1.2% respectively). Conclusion Membership of non‐White ethnic groups and socioeconomic deprivation are important determinants of dementia risk, with effects larger than many of the more established risk factors. These effects cannot be completely accounted for by known modifiable risk factors and further work is required to establish the responsible mechanisms. Depression and diabetes are of greater relative importance, and should be prioritised as targets for dementia prevention in more diverse and deprived populations.