Genome-wide meta-analysis of short-tandem repeats for Parkinson's disease risk using genotype imputation

• Published in: Brain communications Vol. 6; no. 3; p. fcae146
• Main Authors: Ohlei, Olena, Paul, Kimberly, Nielsen, Susan Searles, Gmelin, David, Dobricic, Valerija, Altmann, Vivian, Schilling, Marcel, Bronstein, Jeff M, Franke, Andre, Wittig, Michael, Parkkinen, Laura, Hansen, Johnni, Checkoway, Harvey, Ritz, Beate, Bertram, Lars, Lill, Christina M
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 2024
• Subjects: Original; microsatellites; DNA methylation; short-tandem repeats; Parkinson’s disease; genome-wide association study
• ISSN: 2632-1297; 2632-1297
• DOI: 10.1093/braincomms/fcae146

Idiopathic Parkinson's disease is determined by a combination of genetic and environmental factors. Recently, the first genome-wide association study on short-tandem repeats in Parkinson's disease reported on eight suggestive short-tandem repeat-based risk loci (
= 5.3 × 10
), of which four were novel, i.e. they had not been implicated in Parkinson's disease risk by genome-wide association analyses of single-nucleotide polymorphisms before. Here, we tested these eight candidate short-tandem repeats in a large, independent Parkinson's disease case-control dataset (
= 4757). Furthermore, we combined the results from both studies by meta-analysis resulting in the largest Parkinson's disease genome-wide association study of short-tandem repeats to date (
= 43 844). Lastly, we investigated whether leading short-tandem repeat risk variants exert functional effects on gene expression regulation based on methylation quantitative trait locus data in human 'post-mortem' brain (
= 142). None of the eight previously reported short-tandem repeats were significantly associated with Parkinson's disease in our independent dataset after multiple testing correction (
= 6.25 × 10
). However, we observed modest support for short-tandem repeats near
and
in the updated meta-analyses of all available data. While the genome-wide meta-analysis did not reveal additional study-wide significant (
= 6.3 × 10
) short-tandem repeat signals, we identified seven novel suggestive Parkinson's disease short-tandem repeat risk loci (
= 5.3 × 10
). Of these, especially a short-tandem repeat near
showed consistent evidence for association across datasets.
,
and one novel suggestive locus identified here (
) emerged from colocalization analyses showing evidence for a shared causal short-tandem repeat variant affecting both Parkinson's disease risk and
DNA methylation in brain. Larger studies, ideally using short-tandem repeats called from whole-sequencing data, are needed to more fully investigate their role in Parkinson's disease.