Kia DA, Zhang D, Guelfi S, Manzoni C, Hubbard L, Reynolds RH, Botía J, Ryten M, Ferrari R, Lewis PA, Williams N, Trabzuni D, Hardy J, Wood NW, United Kingdom Brain Expression Consortium (UKBEC) and the International Parkinson’s Disease Genomics Consortium (IPDGC). Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets. JAMA Neurol. 2021 Apr 1;78(4):464-472. PubMed.

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  1. Genome-wide association studies (GWAS) have revolutionized the search for genetic risk factors of human disease, including Parkinson’s disease. However, the translation into biological understanding of disease mechanisms has been lagging behind.

    To improve the understanding of genes and mechanisms underlying PD, here Kia and colleagues have investigated the hypothesis that genes underlying PD influence disease risk by changes in gene expression, splicing, or methylation. They performed a range of complex bioinformatics analyses by combining information from a recent GWAS with relatively large datasets on gene expression, methylation, and gene splicing in the brain.

    The study identified five genes with changes in total gene expression associated with PD risk. At least two of these, GPNMB (Murthy et al., 2017) and RAB29/RAB7L1 (Pihlstrom et al., 2015) have been highlighted as likely PD-related genes in previous studies. The number of genes with altered expression seems low, as it would be expected that many of the possible ways genetic variants influence disease risk would be through gene-expression changes. This may be related to the relatively conservative approach used by the authors. Gene-expression data was taken from two publicly available sources that are based on different technologies, GTEx (RNA-seq) and Braineac (microarray). The authors used two methods, Coloc and TWAS, to test if gene-expression regulation was. Only genes that replicated across the two methods were included.

    Our group recently published results from a study using allelic expression profiling of genes located within PD-associated loci to identify cis-regulatory variation affecting gene expression (Langmyhr et al., 2021). Using this sensitive PCR-based method, allele-specific expression was identified for the majority of tested genes. This 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.

    An intriguing finding by Kia and his colleagues was that the identified gene-expression changes were overall more prevalent in glial cells compared to neurons. This contradicts findings from recent genetic studies. We and others have found enrichment of PD risk variants in regulatory gene regions of neurons, indicating that neurons, and not glial cells, are the primary mediators of genetic risk for PD (Berge-Seidl et al., 2021).

    As the quality and quantity of gene expression data from brain tissue increase, including from single-cell experiments, we can expect a number of studies using similar approaches as Kia and co-workers. This will undoubtedly give new and important insights into disease mechanisms of PD.

    References:

    Murthy MN, Blauwendraat C, UKBEC, Guelfi S, IPDGC, Hardy J, Lewis PA, Trabzuni D. Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson's disease on chromosome 7p15.3. Neurogenetics. 2017 Jul;18(3):121-133. Epub 2017 Apr 8 PubMed.

    Pihlstrøm L, Rengmark A, Bjørnarå KA, Dizdar N, Fardell C, Forsgren L, Holmberg B, Larsen JP, Linder J, Nissbrandt H, Tysnes OB, Dietrichs E, Toft M. Fine mapping and resequencing of the PARK16 locus in Parkinson's disease. J Hum Genet. 2015 Jul;60(7):357-62. Epub 2015 Apr 9 PubMed.

    Langmyhr M, Henriksen SP, Cappelletti C, van de Berg WD, Pihlstrøm L, Toft M. Allele-specific expression of Parkinson's disease susceptibility genes in human brain. Sci Rep. 2021 Jan 12;11(1):504. PubMed.

    Berge-Seidl V, Pihlstrøm L, Toft M. Integrative analysis identifies bHLH transcription factors as contributors to Parkinson's disease risk mechanisms. Sci Rep. 2021 Feb 10;11(1):3502. PubMed.

    View all comments by Mathias Toft

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