• Parkkinen, Laura
• Lill, Christina
• Bertram, Lars
• Checkoway, Harvey
• Bronstein, Jeff M.
• Schilling, Marcel
• Wittig, Michael
• Hansen, Johnni
• Altmann, Vivian
• Gmelin, David
• Dobricic, Valerija
• Paul, Kimberly
• Ritz, Beate
• Nielsen, Susan Searles
• Franke, Andre
• Ohlei, Olena

Abstract

<jats:title>Abstract</jats:title><jats:p>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 (α=5.3×10-6), 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.</jats:p><jats:p>Here, we tested these eight candidate short-tandem repeats in a large, independent Parkinson’s disease case-control dataset (n=4,757). 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 (n=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 (n=142).</jats:p><jats:p>None of the eight previously reported short-tandem repeats were significantly associated with Parkinson’s disease in our independent dataset after multiple testing correction (α=6.25x10-3). However, we observed modest support for short tandem repeats near CCAR2 and NCOR1 in the updated meta-analyses of all available data. While the genome-wide meta-analysis did not reveal additional study-wide significant (α=6.3×10-7) short-tandem repeat signals, we identified seven novel suggestive Parkinson’s disease short-tandem repeat risk loci (α=5.3×10-6). Of these, especially a short-tandem repeat near MEIOSIN showed consistent evidence for association across datasets. CCAR2, NCOR1 and one novel suggestive locus identified here (LINC01012) emerged from colocalization analyses showing evidence for a shared causal short-tandem repeat variant affecting both Parkinson’s disease risk and cis 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.</jats:p>

Topics

• impedance spectroscopy
• chemical ionisation