title: Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson's disease on chromosome 7p15.3.
abstract: Genome wide association studies (GWAS) for Parkinson's disease (PD) have previously revealed a significant association with a locus on chromosome 7p15.3, initially designated as the glycoprotein non-metastatic melanoma protein B (GPNMB) locus. In this study, the functional consequences of this association on expression were explored in depth by integrating different expression quantitative trait locus (eQTL) datasets (Braineac, CAGEseq, GTEx, and Phenotype-Genotype Integrator (PheGenI)). Top risk SNP rs199347 eQTLs demonstrated increased expressions of GPNMB, KLHL7, and NUPL2 with the major allele (AA) in brain, with most significant eQTLs in cortical regions, followed by putamen. In addition, decreased expression of the antisense RNA KLHL7-AS1 was observed in GTEx. Furthermore, rs199347 is an eQTL with long non-coding RNA (AC005082.12) in human tissues other than brain. Interestingly, transcript-specific eQTLs in immune-related tissues (spleen and lymphoblastoid cells) for NUPL2 and KLHL7-AS1 were observed, which suggests a complex functional role of this eQTL in specific tissues, cell types at specific time points. Significantly increased expression of GPNMB linked to rs199347 was consistent across all datasets, and taken in combination with the risk SNP being located within the GPNMB gene, these results suggest that increased expression of GPNMB is the causative link explaining the association of this locus with PD. However, other transcript eQTLs and subsequent functional roles cannot be excluded. This highlights the importance of further investigations to understand the functional interactions between the coding genes, antisense, and non-coding RNA species considering the tissue and cell-type specificity to understand the underlying biological mechanisms in PD.
authors.affiliation: Genetics and Genomics Laboratory, DOS in Genetics and Genomics, University of Mysore, Mysore, Karnataka, 570006, India.|School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AP, UK.
authors.forename: Megha N
authors.initials: MN
authors.lastname: Murthy
authors.affiliation: Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Blauwendraat
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Guelfi
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AP, UK.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lewis
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. d.trabzuni@ucl.ac.uk.|Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia. d.trabzuni@ucl.ac.uk.
authors.forename: Daniah
authors.initials: D
authors.lastname: Trabzuni
mesh_terms: D001921:Brain / Q000378:metabolism; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics; D012306:Risk
chemical_list: C503042:GPNMB protein, human; D008562:Membrane Glycoproteins; D062085:RNA, Long Noncoding
keywords: Antisense and non-coding RNA; Chr7 locus (GPNMB); Human brain expression QTLs; Parkinson’s disease (PD); Risk SNP rs199347