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

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

doi:10.1093/braincomms/fcae146

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

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

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Neurogenetik

5 Zitate (Scopus)

Abstract

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. 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 (α = 6.25 × 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 (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.

Originalsprache	Englisch
Aufsatznummer	fcae146
Zeitschrift	Brain Communications
Jahrgang	6
Ausgabenummer	3
ISSN	2632-1297
DOIs	https://doi.org/10.1093/braincomms/fcae146
Publikationsstatus	Veröffentlicht - 2024

Fördermittel

This study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; LI 2654/2-1, BE 2287/5-1, BE 2287/9-1), the Cure Alzheimer’s Fund and the Michael J. Fox Foundation (MJFF-008994). C.M.L. was supported by the Heisenberg grant of the German Research Foundation (LI 2654/4–1). V.A. received funding from the National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico), Brazil. The authors acknowledge the use of the high-performance environment (‘OmicsCluster’) of the University of Lübeck and for the GHC data the Interdisciplinary Center for Exposures, Diseases, Genomics and Environment of the University of Washington funded by the U.S. National Institutes of Health—National Institute of Environmental Health Sciences (P30ES007033). The PEG and PASIDA studies’ data collection was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health (grant numbers R01ES010544 and R01ES013717) and the American Parkinson's disease Association (grant number 20161386). This study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; LI 2654/2-1, BE 2287/5-1, BE 2287/9-1), the Cure Alzheimer's Fund and the Michael J. Fox Foundation (MJFF-008994). C.M.L. was supported by the Heisenberg grant of the German Research Foundation (LI 2654/4-1). V.A. received funding from the National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico), Brazil. The authors acknowledge the use of the high- performance environment ('OmicsCluster') of the University of Lübeck and for the GHC data the Interdisciplinary Center for Exposures, Diseases, Genomics and Environment of the University of Washington funded by the U.S. National Institutes of Health-National Institute of Environmental Health Sciences (P30ES007033). The PEG and PASIDA studies' data collection was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health (grant numbers R01ES010544 and R01ES013717) and the American Parkinson's disease Association (grant number 20161386).

Träger	Trägernummer
Deutsche Forschungsgemeinschaft	LI 2654/2-1
National Institutes of Health-National Institute of Environmental Health Sciences	P30ES007033
Michael J. Fox Foundation for Parkinson's Research	MJFF-008994, LI 2654/4–1
American Parkinson Disease Association	20161386
National Institute of Environmental Health Sciences	R01ES010544, R01ES013717, P30ES007033

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Querschnittsbereich: Medizinische Genetik

DFG-Fachsystematik

2.23-06 Molekulare und zelluläre Neurologie und Neuropathologie

Dokumente

10.1093/braincomms/fcae146

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Ohlei, O., Paul, K., Nielsen, S. S., Gmelin, D., Dobricic, V., Altmann, V., Schilling, M., Bronstein, J. M., Franke, A., Wittig, M., Parkkinen, L., Hansen, J., Checkoway, H., Ritz, B., Bertram, L., & Lill, C. M. (2024). Genome-wide meta-analysis of short-tandem repeats for Parkinson's disease risk using genotype imputation. Brain Communications, 6(3), Artikel fcae146. https://doi.org/10.1093/braincomms/fcae146

@article{08478201075b438a997804a733d9f5e4,

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

abstract = "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. 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 (α = 6.25 × 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 (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.",

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

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.",

year = "2024",

doi = "10.1093/braincomms/fcae146",

language = "English",

volume = "6",

journal = "Brain Communications",

issn = "2632-1297",

publisher = "Oxford University Press",

number = "3",

}

Ohlei, O, Paul, K, Nielsen, SS, Gmelin, D , Dobricic, V, Altmann, V, Schilling, M, Bronstein, JM, Franke, A, Wittig, M, Parkkinen, L, Hansen, J, Checkoway, H, Ritz, B, Bertram, L & Lill, CM 2024, 'Genome-wide meta-analysis of short-tandem repeats for Parkinson's disease risk using genotype imputation', Brain Communications, Jg. 6, Nr. 3, fcae146. https://doi.org/10.1093/braincomms/fcae146

TY - JOUR

T1 - Genome-wide meta-analysis of short-tandem repeats for Parkinson's disease risk using genotype imputation

AU - Ohlei, Olena

AU - Paul, Kimberly

AU - Nielsen, Susan Searles

AU - Gmelin, David

AU - Dobricic, Valerija

AU - Altmann, Vivian

AU - Schilling, Marcel

AU - Bronstein, Jeff M.

AU - Franke, Andre

AU - Wittig, Michael

AU - Parkkinen, Laura

AU - Hansen, Johnni

AU - Checkoway, Harvey

AU - Ritz, Beate

AU - Bertram, Lars

AU - Lill, Christina M.

PY - 2024

Y1 - 2024

N2 - 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. 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 (α = 6.25 × 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 (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.

AB - 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. 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 (α = 6.25 × 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 (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.

UR - https://www.scopus.com/pages/publications/85196071343

U2 - 10.1093/braincomms/fcae146

DO - 10.1093/braincomms/fcae146

M3 - Journal articles

AN - SCOPUS:85196071343

SN - 2632-1297

VL - 6

JO - Brain Communications

JF - Brain Communications

IS - 3

M1 - fcae146

ER -

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

Abstract

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