Dataset Information

Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease.

ABSTRACT: Despite substantial progress, causal variants are identified only for a minority of familial Parkinson's disease (PD) cases, leaving high-risk pathogenic variants unidentified^1,2. To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a novel PD gene identifying c.213C > G/p.S71R as a high-risk variant presenting in ~0.7% of familial PD cases while observed in only 0.004% of controls (odds ratio of 65.5). This variant was confirmed in all cases via Sanger sequencing and segregated with PD in three families. RAB32 encodes a small GTPase known to interact with LRRK2 (refs. ^3,4). Functional analyses showed that RAB32 S71R increases LRRK2 kinase activity, as indicated by increased autophosphorylation of LRRK2 S1292. Here our results implicate mutant RAB32 in a key pathological mechanism in PD-LRRK2 kinase activity^5-7-and thus provide novel insights into the mechanistic connections between RAB family biology, LRRK2 and PD risk.

SUBMITTER: Hop PJ

PROVIDER: S-EPMC11250361 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease.

Hop Paul J PJ Lai Dongbing D Keagle Pamela J PJ Baron Desiree M DM Kenna Brendan J BJ Kooyman Maarten M Shankaracharya Halter Cheryl C Straniero Letizia L Asselta Rosanna R Bonvegna Salvatore S Soto-Beasley Alexandra I AI Wszolek Zbigniew K ZK Uitti Ryan J RJ Isaias Ioannis Ugo IU Pezzoli Gianni G Ticozzi Nicola N Ross Owen A OA Veldink Jan H JH Foroud Tatiana M TM Kenna Kevin P KP Landers John E JE

Nature genetics 20240610 7

Despite substantial progress, causal variants are identified only for a minority of familial Parkinson's disease (PD) cases, leaving high-risk pathogenic variants unidentified<sup>1,2</sup>. To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a novel PD gene identifying c.213C > G/p.S71R as a high-risk variant presenting in ~0.7% of familial PD cases while observed in only 0.004% o ...[more]

PMID: 38858457

Similar Datasets

Project description:BackgroundParkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD.MethodsAffected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed.FindingsWe found RAB32 c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. RAB32 Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, RAB32 Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase.InterpretationOur study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD.FundingNational Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

Project description:BackgroundA relevant part of the genetic architecture of complex traits is still unknown; despite the discovery of many disease-associated common variants. Polygenic risk score (PRS) models are based on the evaluation of the additive effects attributable to common variants and have been successfully implemented to assess the genetic susceptibility for many phenotypes. In contrast, burden tests are often used to identify an enrichment of rare deleterious variants in specific genes. Both kinds of genetic contributions are typically analyzed independently. Many studies suggest that complex phenotypes are influenced by both low effect common variants and high effect rare deleterious variants. The aim of this paper is to integrate the effect of both common and rare functional variants for a more comprehensive genetic risk modeling.MethodsWe developed a framework combining gene-based scores based on the enrichment of rare functionally relevant variants with genome-wide PRS based on common variants for association analysis and prediction models. We applied our framework on UK Biobank dataset with genotyping and exome data and considered 28 blood biomarkers levels as target phenotypes. For each biomarker, an association analysis was performed on full cohort using gene-based scores (GBS). The cohort was then split into 3 subsets for PRS construction and feature selection, predictive model training, and independent evaluation, respectively. Prediction models were generated including either PRS, GBS or both (combined).ResultsAssociation analyses of the cohort were able to detect significant genes that were previously known to be associated with different biomarkers. Interestingly, the analyses also revealed heterogeneous effect sizes and directionality highlighting the complexity of the blood biomarkers regulation. However, the combined models for many biomarkers show little or no improvement in prediction accuracy compared to the PRS models.ConclusionThis study shows that rare variants play an important role in the genetic architecture of complex multifactorial traits such as blood biomarkers. However, while rare deleterious variants play a strong role at an individual level, our results indicate that classical common variant based PRS might be more informative to predict the genetic susceptibility at the population level.

Dataset Information

Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease.

Publications

Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets