Abstract
Genome-wide association study (GWAS) has seen great strides in revealing initial insights into the genetic architecture of Parkinson’s disease (PD). Since GWAS signals often reside in non-coding regions, relatively few of the associations have implicated specific biological mechanisms. Here, we aimed to integrate the GWAS results with large-scale expression quantitative trait loci (eQTL) in 13 brain tissues to identify candidate causal genes for PD. We conducted a transcriptome-wide association study (TWAS) for PD using the summary statistics of over 480,000 individuals from the most recent PD GWAS. We identified 18 genes significantly associated with PD after Bonferroni corrections. The most significant gene, LRRC37A2, was associated with PD in all 13 brain tissues, such as in the hypothalamus (P = 6.12 × 10−22) and nucleus accumbens basal ganglia (P = 5.62 × 10−21). We also identified eight conditionally independent genes, including four new genes at known PD loci: CD38, LRRC37A2, RNF40, and ZSWIM7. Through conditional analyses, we demonstrated that several of the GWAS significant signals on PD could be driven by genetically regulated gene expression. The most significant TWAS gene LRRC37A2 accounts for 0.855 of the GWAS signal at its loci, and ZSWIM7 accounts for all the GWAS signals at its loci. We further identified several phenotypes previously associated with PD by querying the single nucleotide polymorphisms (SNPs) in the final model of the identified genes in phenome databases. In conclusion, we prioritized genes that are likely to affect PD by using a TWAS approach and identified phenotypes associated with PD.
Highlights
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder after Alzheimer’s disease, characterized by the loss of nigrostriatal neurons in the substantia nigra[1].PD is more common in the elderly, and the prevalence increased from 1% in people over 60 years to 3–4% in those over 80 years[2]
Associations[18], we only focused on genes whose heritability did not overlap with zero with 95% confidence interval
For regions where TWAS identified multiple associated features, we jointly modeled these genes to determine the independent signals
Summary
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder after Alzheimer’s disease, characterized by the loss of nigrostriatal neurons in the substantia nigra[1]. PD is more common in the elderly, and the prevalence increased from 1% in people over 60 years to 3–4% in those over 80 years[2]. Based on twin and family studies, the heritability of PD has been estimated to be at least 27% and up to 60%3,4, suggesting a substantial involvement of genetic factors drives the phenotypic variance. Genome-wide association study (GWAS) has seen great strides and invaluable utilities in revealing initial insights into PD’s genetic architecture. Together, associated loci represent only a small fraction of PD’s genetic etiology, leaving a substantial proportion of genetic risk factors uncharacterized[6]
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