TY - JOUR
T1 - Allele-specific expression of Parkinson’s disease susceptibility genes in human brain
AU - Langmyhr, Margrete
AU - Henriksen, Sandra Pilar
AU - Cappelletti, Chiara
AU - van de Berg, Wilma D. J.
AU - Pihlstrom, Lasse
AU - Toft, Mathias
N1 - Funding Information: We thank Tone Berge and Steffan Bos-Haugen for helpful advice. We thank Angela Ingrassia and Yvonne de Gier for processing the brain tissue samples for DNA and RNA isolation. This work was supported by grants from the South-Eastern Norway Regional Health Authority (Project No. 2016057 to MT), Research Council of Norway (Project No. 250597 to MT) and Norwegian Health Association (to LP). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/12
Y1 - 2021/1/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85099173341&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41598-020-79990-9
DO - https://doi.org/10.1038/s41598-020-79990-9
M3 - Article
C2 - 33436766
SN - 2045-2322
VL - 11
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 504
ER -