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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/214830
Genome-wide meta-analysis of short-tandem repeats for Parkinson's disease risk using genotype imputation
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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 (alpha = 5.3 x 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. Here, we tested these eight candidate short-tandem repeats in a large, independent Parkinson's disease case-control dataset (n = 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 (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). None of the eight previously reported short-tandem repeats were significantly associated with Parkinson's disease in our independent dataset after multiple testing correction (alpha = 6.25 x 10-3). 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 (alpha = 6.3 x 10-7) short-tandem repeat signals, we identified seven novel suggestive Parkinson's disease short-tandem repeat risk loci (alpha = 5.3 x 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. Ohlei et al.'s updated genome-wide association study on short-tandem repeats (STRs) in 43 844 Parkinson's disease cases and controls supported two (CCAR2 and NCOR1) of eight previously reported risk STRs. Seven novel suggestive risk loci were identified, including a STR near MEIOSIN. Several STRs may act via DNA methylation changes. Graphical Abstract
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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.. Genome-wide meta-analysis of short-tandem repeats for Parkinson's disease risk using genotype imputation. _Brain Communications_. 2024. Vol. 6, núm. 3. [consulta: 10 de gener de 2026]. ISSN: 2632-1297. [Disponible a: https://hdl.handle.net/2445/214830]