Allele-specific expression of Parkinson’s disease susceptibility genes in human brain
Abstract Genome-wide association studies have identified genetic variation in genomic loci associated with susceptibility to Parkinson’s disease (PD), the most common neurodegenerative movement disorder worldwide. We used allelic expression profiling of genes located within PD-associated loci to ide...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-79990-9 |
| _version_ | 1818430667178901504 |
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| author | Margrete Langmyhr Sandra Pilar Henriksen Chiara Cappelletti Wilma D. J. van de Berg Lasse Pihlstrøm Mathias Toft |
| author_facet | Margrete Langmyhr Sandra Pilar Henriksen Chiara Cappelletti Wilma D. J. van de Berg Lasse Pihlstrøm Mathias Toft |
| author_sort | Margrete Langmyhr |
| collection | DOAJ |
| description | Abstract Genome-wide association studies have identified genetic variation in genomic loci associated with susceptibility to Parkinson’s disease (PD), the most common neurodegenerative movement disorder worldwide. We used allelic expression profiling of genes located within PD-associated loci to identify cis-regulatory variation affecting gene expression. DNA and RNA were extracted from post-mortem superior frontal gyrus tissue and whole blood samples from PD patients and controls. The relative allelic expression of transcribed SNPs in 12 GWAS risk genes was analysed by real-time qPCR. Allele-specific expression was identified for 9 out of 12 genes tested (GBA, TMEM175, RAB7L1, NUCKS1, MCCC1, BCKDK, ZNF646, LZTS3, and WDHD1) in brain tissue samples. Three genes (GPNMB, STK39 and SIPA1L2) did not show significant allele-specific effects. Allele-specific effects were confirmed in whole blood for three genes (BCKDK, LZTS3 and MCCC1), whereas two genes (RAB7L1 and NUCKS1) showed brain-specific allelic expression. Our study supports the hypothesis that changes to the cis-regulation of gene expression is a major mechanism behind a large proportion of genetic associations in PD. Interestingly, allele-specific expression was also observed for coding variants believed to be causal variants (GBA and TMEM175), indicating that splicing and other regulatory mechanisms may be involved in disease development. |
| first_indexed | 2024-12-14T15:37:03Z |
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| id | doaj.art-911000b21a6c43fa84edbe5866d2fd5f |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T15:37:03Z |
| publishDate | 2021-01-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj.art-911000b21a6c43fa84edbe5866d2fd5f2022-12-21T22:55:42ZengNature PortfolioScientific Reports2045-23222021-01-0111111210.1038/s41598-020-79990-9Allele-specific expression of Parkinson’s disease susceptibility genes in human brainMargrete Langmyhr0Sandra Pilar Henriksen1Chiara Cappelletti2Wilma D. J. van de Berg3Lasse Pihlstrøm4Mathias Toft5Department of Neurology, Oslo University HospitalDepartment of Neurology, Oslo University HospitalDepartment of Mechanical, Electronic and Chemical Engineering, OsloMet – Oslo Metropolitan UniversityDepartment of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam Neuroscience, Amsterdam UMC, Location VU Medical CenterDepartment of Neurology, Oslo University HospitalDepartment of Neurology, Oslo University HospitalAbstract Genome-wide association studies have identified genetic variation in genomic loci associated with susceptibility to Parkinson’s disease (PD), the most common neurodegenerative movement disorder worldwide. We used allelic expression profiling of genes located within PD-associated loci to identify cis-regulatory variation affecting gene expression. DNA and RNA were extracted from post-mortem superior frontal gyrus tissue and whole blood samples from PD patients and controls. The relative allelic expression of transcribed SNPs in 12 GWAS risk genes was analysed by real-time qPCR. Allele-specific expression was identified for 9 out of 12 genes tested (GBA, TMEM175, RAB7L1, NUCKS1, MCCC1, BCKDK, ZNF646, LZTS3, and WDHD1) in brain tissue samples. Three genes (GPNMB, STK39 and SIPA1L2) did not show significant allele-specific effects. Allele-specific effects were confirmed in whole blood for three genes (BCKDK, LZTS3 and MCCC1), whereas two genes (RAB7L1 and NUCKS1) showed brain-specific allelic expression. Our study supports the hypothesis that changes to the cis-regulation of gene expression is a major mechanism behind a large proportion of genetic associations in PD. Interestingly, allele-specific expression was also observed for coding variants believed to be causal variants (GBA and TMEM175), indicating that splicing and other regulatory mechanisms may be involved in disease development.https://doi.org/10.1038/s41598-020-79990-9 |
| spellingShingle | Margrete Langmyhr Sandra Pilar Henriksen Chiara Cappelletti Wilma D. J. van de Berg Lasse Pihlstrøm Mathias Toft Allele-specific expression of Parkinson’s disease susceptibility genes in human brain Scientific Reports |
| title | Allele-specific expression of Parkinson’s disease susceptibility genes in human brain |
| title_full | Allele-specific expression of Parkinson’s disease susceptibility genes in human brain |
| title_fullStr | Allele-specific expression of Parkinson’s disease susceptibility genes in human brain |
| title_full_unstemmed | Allele-specific expression of Parkinson’s disease susceptibility genes in human brain |
| title_short | Allele-specific expression of Parkinson’s disease susceptibility genes in human brain |
| title_sort | allele specific expression of parkinson s disease susceptibility genes in human brain |
| url | https://doi.org/10.1038/s41598-020-79990-9 |
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