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Evaluation of Parkinson disease risk variants as expression-QTLs.

ABSTRACT: The recent Parkinson Disease GWAS Consortium meta-analysis and replication study reports association at several previously confirmed risk loci SNCA, MAPT, GAK/DGKQ, and HLA and identified a novel risk locus at RIT2. To further explore functional consequences of these associations, we investigated modification of gene expression in prefrontal cortex brain samples of pathologically confirmed PD cases (N = 26) and controls (N = 24) by 67 associated SNPs in these 5 loci. Association between the eSNPs and expression was evaluated using a 2-degrees of freedom test of both association and difference in association between cases and controls, adjusted for relevant covariates. SNPs at each of the 5 loci were tested for cis-acting effects on all probes within 250 kb of each locus. Trans-effects of the SNPs on the 39,122 probes passing all QC on the microarray were also examined. From the analysis of cis-acting SNP effects, several SNPs in the MAPT region show significant association to multiple nearby probes, including two strongly correlated probes targeting the gene LOC644246 and the duplicated genes LRRC37A and LRRC37A2, and a third uncorrelated probe targeting the gene DCAKD. Significant cis-associations were also observed between SNPs and two probes targeting genes in the HLA region on chromosome 6. Expanding the association study to examine trans effects revealed an additional 23 SNP-probe associations reaching statistical significance (p<2.8 × 10(-8)) including SNPs from the SNCA, MAPT and RIT2 regions. These findings provide additional context for the interpretation of PD associated SNPs identified in recent GWAS as well as potential insight into the mechanisms underlying the observed SNP associations.

SUBMITTER: Latourelle JC

PROVIDER: S-EPMC3465315 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Evaluation of Parkinson disease risk variants as expression-QTLs.

Latourelle Jeanne C JC Dumitriu Alexandra A Hadzi Tiffany C TC Beach Thomas G TG Myers Richard H RH

PloS one 20121005 10

The recent Parkinson Disease GWAS Consortium meta-analysis and replication study reports association at several previously confirmed risk loci SNCA, MAPT, GAK/DGKQ, and HLA and identified a novel risk locus at RIT2. To further explore functional consequences of these associations, we investigated modification of gene expression in prefrontal cortex brain samples of pathologically confirmed PD cases (N = 26) and controls (N = 24) by 67 associated SNPs in these 5 loci. Association between the eSNP ...[more]

PMID: 23071545

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Project description:ImportanceLoneliness is associated with morbidity and mortality, including higher risk of neurodegenerative diseases. To our knowledge, no study has examined whether the association between loneliness and detrimental outcomes extends to Parkinson disease (PD).ObjectiveTo assess whether loneliness is associated with risk of incident PD and whether the association is independent of other risk factors or modified by age, sex, and genetic vulnerability.Design, setting, and participantsThis prospective cohort study included a population-based sample of UK Biobank participants aged 38 to 73 years with loneliness data and without a diagnosis of PD at baseline who were first assessed from March 13, 2006, to October 1, 2010, and followed up to October 9, 2021.ExposureFeeling lonely and covariates that are known risk factors for or prodromal features of PD.Main outcome and measureIncident PD was ascertained through UK National Health Service health records.ResultsOf 491 603 participants (mean [SD] age, 56.54 [8.09] years; 54.4% female), 2822 developed PD during the 15-year follow-up. Individuals who reported being lonely had a higher risk of PD (hazard ratio [HR], 1.37; 95% CI, 1.25-1.51), an association that remained after accounting for demographic factors, socioeconomic status, social isolation, PD polygenetic risk score, smoking, physical activity, body mass index, diabetes, hypertension, stroke, myocardial infarction, depression, and ever seeing a psychiatrist (fully adjusted model: HR 1.25; 95% CI, 1.12-1.39). The association between loneliness and incident PD was not moderated by sex (HR for interaction, 0.98; 95% CI, 95% CI, 0.81-1.18), age (HR for interaction, 0.99; 95% CI, 0.98-1.01), or polygenic risk score (HR for interaction, 0.93; 95% CI, 0.85-1.02). Contrary to expectations for a prodromal syndrome, when stratified by time, loneliness was not associated with risk for incident PD during the first 5 years (HR, 1.15; 95% CI, 0.91-1.45) but was associated with PD risk during the subsequent 10 years (HR, 1.32; 95% CI, 1.19-1.46).Conclusions and relevanceThis large cohort study found that loneliness was associated with risk of incident PD across demographic groups and independent of depression and other prominent risk factors and genetic risk. The findings add to the evidence that loneliness is a substantial psychosocial determinant of health.

Project description:Few epidemiologic studies have evaluated the effects of air pollution on the risk of Parkinson disease (PD).We investigated the associations of long-term residential concentrations of ambient particulate matter (PM) < 10 ?m in diameter (PM10) and < 2.5 ?m in diameter (PM2.5) and nitrogen dioxide (NO2) in relation to PD risk.Our nested case-control analysis included 1,556 self-reported physician-diagnosed PD cases identified between 1995 and 2006 and 3,313 controls frequency-matched on age, sex, and race. We geocoded home addresses reported in 1995-1996 and estimated the average ambient concentrations of PM10, PM2.5, and NO2 using a national fine-scale geostatistical model incorporating roadway information and other geographic covariates. Air pollutant exposures were analyzed as both quintiles and continuous variables, adjusting for matching variables and potential confounders.We observed no statistically significant overall association between PM or NO2 exposures and PD risk. However, in preplanned subgroup analyses, a higher risk of PD was associated with higher exposure to PM10 (ORQ5 vs. Q1 = 1.65; 95% CI: 1.11, 2.45; p-trend = 0.02) among women, and with higher exposure to PM2.5 (ORQ5 vs. Q1 = 1.29; 95% CI: 0.94, 1.76; p-trend = 0.04) among never smokers. In post hoc analyses among female never smokers, both PM2.5 (ORQ5 vs. Q1 = 1.79; 95% CI: 1.01, 3.17; p-trend = 0.05) and PM10 (ORQ5 vs. Q1 = 2.34; 95% CI: 1.29, 4.26; p-trend = 0.01) showed positive associations with PD risk. Analyses based on continuous exposure variables generally showed similar but nonsignificant associations.Overall, we found limited evidence for an association between exposures to ambient PM10, PM2.5, or NO2 and PD risk. The suggestive evidence that exposures to PM2.5 and PM10 may increase PD risk among female never smokers warrants further investigation. Citation: Liu R, Young MT, Chen JC, Kaufman JD, Chen H. 2016. Ambient air pollution exposures and risk of Parkinson disease. Environ Health Perspect 124:1759-1765;?http://dx.doi.org/10.1289/EHP135.

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Evaluation of Parkinson disease risk variants as expression-QTLs.

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Evaluation of Parkinson disease risk variants as expression-QTLs.

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