Dataset Information

Genome-wide assessment of Parkinson's disease in a Southern Spanish population.

ABSTRACT: Here, we set out to study the genetic architecture of Parkinson's disease (PD) through a Genome-Wide Association Study in a Southern Spanish population. About 240 PD cases and 192 controls were genotyped on the NeuroX array. We estimated genetic variation associated with PD risk and age at onset (AAO). Risk profile analyses for PD and AAO were performed using a weighted genetic risk score. Total heritability was estimated by genome-wide complex trait analysis. Rare variants were screened with single-variant and burden tests. We also screened for variation in known PD genes. Finally, we explored runs of homozygosity and structural genomic variations. We replicate PD association (uncorrected p-value < 0.05) at the following loci: ACMSD/TMEM163, MAPT, STK39, MIR4697, and SREBF/RAI1. Subjects in the highest genetic risk score quintile showed significantly increased risk of PD versus the lowest quintile (odds ratio = 3.6, p-value < 4e(-7)), but no significant difference in AAO. We found evidence of runs of homozygosity in 2 PD-associated regions: one intersecting the HLA-DQB1 gene in 6 patients and 1 control; and another intersecting the GBA-SYT11 gene in PD case. The GBA N370S and the LRRK2 G2019S variants were found in 8 and 7 cases, respectively, replicating previous work. A structural variant was found in 1 case in the PARK2 gene locus. This current work represents a comprehensive assessment at a genome-wide level characterizing a novel population in PD genetics.

SUBMITTER: Bandres-Ciga S

PROVIDER: S-EPMC4976046 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Genome-wide assessment of Parkinson's disease in a Southern Spanish population.

Bandrés-Ciga Sara S Price Timothy Ryan TR Barrero Francisco Javier FJ Escamilla-Sevilla Francisco F Pelegrina Javier J Arepalli Sampath S Hernández Dena D Gutiérrez Blanca B Cervilla Jorge J Rivera Margarita M Rivera Alberto A Ding Jing-Hui JH Vives Francisco F Nalls Michael M Singleton Andrew A Durán Raquel R

Neurobiology of aging 20160611

Here, we set out to study the genetic architecture of Parkinson's disease (PD) through a Genome-Wide Association Study in a Southern Spanish population. About 240 PD cases and 192 controls were genotyped on the NeuroX array. We estimated genetic variation associated with PD risk and age at onset (AAO). Risk profile analyses for PD and AAO were performed using a weighted genetic risk score. Total heritability was estimated by genome-wide complex trait analysis. Rare variants were screened with si ...[more]

PMID: 27393345

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Project description:To date, nine Parkinson disease (PD) genome-wide association studies in North American, European and Asian populations have been published. The majority of studies have confirmed the association of the previously identified genetic risk factors, SNCA and MAPT, and two studies have identified three new PD susceptibility loci/genes (PARK16, BST1 and HLA-DRB5). In a recent meta-analysis of datasets from five of the published PD GWAS an additional 6 novel candidate genes (SYT11, ACMSD, STK39, MCCC1/LAMP3, GAK and CCDC62/HIP1R) were identified. Collectively the associations identified in these GWAS account for only a small proportion of the estimated total heritability of PD suggesting that an 'unknown' component of the genetic architecture of PD remains to be identified.We applied a GWAS approach to a relatively homogeneous Ashkenazi Jewish (AJ) population from New York to search for both 'rare' and 'common' genetic variants that confer risk of PD by examining any SNPs with allele frequencies exceeding 2%. We have focused on a genetic isolate, the AJ population, as a discovery dataset since this cohort has a higher sharing of genetic background and historically experienced a significant bottleneck. We also conducted a replication study using two publicly available datasets from dbGaP. The joint analysis dataset had a combined sample size of 2,050 cases and 1,836 controls.We identified the top 57 SNPs showing the strongest evidence of association in the AJ dataset (p < 9.9 × 10(-5)). Six SNPs located within gene regions had positive signals in at least one other independent dbGaP dataset: LOC100505836 (Chr3p24), LOC153328/SLC25A48 (Chr5q31.1), UNC13B (9p13.3), SLCO3A1(15q26.1), WNT3(17q21.3) and NSF (17q21.3). We also replicated published associations for the gene regions SNCA (Chr4q21; rs3775442, p = 0.037), PARK16 (Chr1q32.1; rs823114 (NUCKS1), p = 6.12 × 10(-4)), BST1 (Chr4p15; rs12502586, p = 0.027), STK39 (Chr2q24.3; rs3754775, p = 0.005), and LAMP3 (Chr3; rs12493050, p = 0.005) in addition to the two most common PD susceptibility genes in the AJ population LRRK2 (Chr12q12; rs34637584, p = 1.56 × 10(-4)) and GBA (Chr1q21; rs2990245, p = 0.015).We have demonstrated the utility of the AJ dataset in PD candidate gene and SNP discovery both by replication in dbGaP datasets with a larger sample size and by replicating association of previously identified PD susceptibility genes. Our GWAS study has identified candidate gene regions for PD that are implicated in neuronal signalling and the dopamine pathway.

Project description:BackgroundParkinson's disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome-wide association studies. The most recent large-scale PD genome-wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome-wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus.MethodsWe included all significant genome-wide signals from multiple recent PD genome-wide association studies including themost recent PD risk genome-wide association study, age-at-onset genome-wide association study, progression genome-wide association study, and Asian population PD risk genome-wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self-ranked criteria. Multiple databases were queried for each gene to collect additional causal data.ResultsWe created a PD genome-wide association study browser tool (https://pdgenetics.shinyapps.io/GWASBrowser/) to assist the PD research community with the prioritization of genes for follow-up functional studies to identify potential therapeutic targets.ConclusionsOur PD genome-wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large-scale PD genome-wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Dataset Information

Genome-wide assessment of Parkinson's disease in a Southern Spanish population.

Publications

Genome-wide assessment of Parkinson's disease in a Southern Spanish population.

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