Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors

Abstract

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.

Transitioning from Subtyping to Precision Medicine in Parkinson's Disease: A Purpose‐Driven Approach

“…In turn, this will enable the collection of data through consortia to support large‐scale analyses of relationships between biological profiles and treatment response. Analogous efforts have been successful in uncovering genetic underpinnings of disease (MEGASTROKE, 35 IPDGC, 35,36 GP2 37 ).…”

Genetic modifiers of rare variants in monogenic developmental disorder loci

“…The related common variant burden has been shown to affect the phenotype in carriers of such variants 5 , 26 , suggesting that the cumulative effect of common variants can modify the penetrance of rare variants in such phenotypes, even when the primary cause is considered monogenic. While the impact of common variants on overall phenotypic expressivity has been examined for several neuropsychiatric 25 , 27 , 28 and other disease cohorts 29 – 31 , the modification of rare variant penetrance by other rare genetic variants has not been widely investigated because of the large cohort sizes required. Here, we present an analysis of common and rare variant burden in 419,854 adults from the UK Biobank (UKB) 32 .…”

Parkinson’s Disease is Predominantly a Genetic Disease

“…Outside the PD field, it has been suggested that PRSs for common diseases such as coronary artery disease and type 2 diabetes, utilizing much larger sample sizes and improved algorithms, can identify individuals with risk equivalent to monogenic mutations [ 70 ] (although others have argued that the true effect size is likely to be much more modest [ 71–74 ]). Recently, research on genetic resilience factors that mitigate the effects of risk/pathogenic loci and reduce the susceptibility to PD is also emerging from GWA analyses [ 75 ].…”