The Role of Rare Coding Variants in Parkinson's Disease GWAS Loci
Introduction: Genome-wide association studies (GWAS) have identified multiple loci associated with Parkinson's disease (PD) risk. The presence of rare variants within these loci that may account for the increased susceptibility requires further investigation.Methods: Using exome sequencing, we...
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| Format: | Article |
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Frontiers Media S.A.
2019-12-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2019.01284/full |
| _version_ | 1828473086276534272 |
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| author | Elisabeth Luisa Germer Sophie Imhoff Carles Vilariño-Güell Meike Kasten Philip Seibler Norbert Brüggemann International Parkinson’s Disease Genomics Consortium Christine Klein Joanne Trinh |
| author_facet | Elisabeth Luisa Germer Sophie Imhoff Carles Vilariño-Güell Meike Kasten Philip Seibler Norbert Brüggemann International Parkinson’s Disease Genomics Consortium Christine Klein Joanne Trinh |
| author_sort | Elisabeth Luisa Germer |
| collection | DOAJ |
| description | Introduction: Genome-wide association studies (GWAS) have identified multiple loci associated with Parkinson's disease (PD) risk. The presence of rare variants within these loci that may account for the increased susceptibility requires further investigation.Methods: Using exome sequencing, we performed a comprehensive rare variant screen of genes located within 56 novel PD loci. We first analyzed exomes from 109 subjects in the discovery cohort (85 diagnosed with PD and 24 healthy controls) and filtered for rare coding variants with minor allele frequency <0.01 and combined annotation-dependent depletion > 15. Further investigation of exome data from a replication cohort of 2,859 European patients with PD (International Parkinson's Disease Genomics Consortium) and 24,146 non-Finnish European controls from gnomAD were used for association testing of specific rare variants found in the discovery cohort.Results: Our genetic screening identified 54 potential disease-relevant variants in 71 genes in 109 subjects. Six out of 54 variants were found in two or more patients and were not observed in healthy controls: DNAH1 p.A3639T, STAB1 p.S1089G, ANK2 p.V3634D, ANK2 p.R3906W, SH3GL2 p.G276V, and NOD2 p.G908R. Replication in the International Parkinson's Disease Genomics Consortium (IPDGC) confirmed the association with PD risk for three out of the six identified variants (STAB1 p.S1089G, SH3GL2 p.G276V, and NOD2 p.G908R) (p < 10−3).Conclusion: Our study suggests that some of the associations identified in PD risk loci can be ascribed to rare variants with likely functional effects that modify PD risk. |
| first_indexed | 2024-12-11T05:39:20Z |
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| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-11T05:39:20Z |
| publishDate | 2019-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-b61e1547d5324dd78906262d7cfa940d2022-12-22T01:19:11ZengFrontiers Media S.A.Frontiers in Neurology1664-22952019-12-011010.3389/fneur.2019.01284496106The Role of Rare Coding Variants in Parkinson's Disease GWAS LociElisabeth Luisa Germer0Sophie Imhoff1Carles Vilariño-Güell2Meike Kasten3Philip Seibler4Norbert Brüggemann5International Parkinson’s Disease Genomics ConsortiumChristine Klein6Joanne Trinh7Institute of Neurogenetics, University of Lübeck, Lübeck, GermanyInstitute of Neurogenetics, University of Lübeck, Lübeck, GermanyDepartment of Medical Genetics, Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, CanadaInstitute of Neurogenetics, University of Lübeck, Lübeck, GermanyInstitute of Neurogenetics, University of Lübeck, Lübeck, GermanyInstitute of Neurogenetics, University of Lübeck, Lübeck, GermanyInstitute of Neurogenetics, University of Lübeck, Lübeck, GermanyInstitute of Neurogenetics, University of Lübeck, Lübeck, GermanyIntroduction: Genome-wide association studies (GWAS) have identified multiple loci associated with Parkinson's disease (PD) risk. The presence of rare variants within these loci that may account for the increased susceptibility requires further investigation.Methods: Using exome sequencing, we performed a comprehensive rare variant screen of genes located within 56 novel PD loci. We first analyzed exomes from 109 subjects in the discovery cohort (85 diagnosed with PD and 24 healthy controls) and filtered for rare coding variants with minor allele frequency <0.01 and combined annotation-dependent depletion > 15. Further investigation of exome data from a replication cohort of 2,859 European patients with PD (International Parkinson's Disease Genomics Consortium) and 24,146 non-Finnish European controls from gnomAD were used for association testing of specific rare variants found in the discovery cohort.Results: Our genetic screening identified 54 potential disease-relevant variants in 71 genes in 109 subjects. Six out of 54 variants were found in two or more patients and were not observed in healthy controls: DNAH1 p.A3639T, STAB1 p.S1089G, ANK2 p.V3634D, ANK2 p.R3906W, SH3GL2 p.G276V, and NOD2 p.G908R. Replication in the International Parkinson's Disease Genomics Consortium (IPDGC) confirmed the association with PD risk for three out of the six identified variants (STAB1 p.S1089G, SH3GL2 p.G276V, and NOD2 p.G908R) (p < 10−3).Conclusion: Our study suggests that some of the associations identified in PD risk loci can be ascribed to rare variants with likely functional effects that modify PD risk.https://www.frontiersin.org/article/10.3389/fneur.2019.01284/fullParkinson's diseaseGWASrare variants association analysesexome analysisSTAB1SH3GL2 |
| spellingShingle | Elisabeth Luisa Germer Sophie Imhoff Carles Vilariño-Güell Meike Kasten Philip Seibler Norbert Brüggemann International Parkinson’s Disease Genomics Consortium Christine Klein Joanne Trinh The Role of Rare Coding Variants in Parkinson's Disease GWAS Loci Frontiers in Neurology Parkinson's disease GWAS rare variants association analyses exome analysis STAB1 SH3GL2 |
| title | The Role of Rare Coding Variants in Parkinson's Disease GWAS Loci |
| title_full | The Role of Rare Coding Variants in Parkinson's Disease GWAS Loci |
| title_fullStr | The Role of Rare Coding Variants in Parkinson's Disease GWAS Loci |
| title_full_unstemmed | The Role of Rare Coding Variants in Parkinson's Disease GWAS Loci |
| title_short | The Role of Rare Coding Variants in Parkinson's Disease GWAS Loci |
| title_sort | role of rare coding variants in parkinson s disease gwas loci |
| topic | Parkinson's disease GWAS rare variants association analyses exome analysis STAB1 SH3GL2 |
| url | https://www.frontiersin.org/article/10.3389/fneur.2019.01284/full |
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