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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-017-0514-8) contains supplementary material, which is available to authorized users.

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

“…The strong association between several SNPs in high LD with rs564309 and decreasing TRIM11 and TRIM17 expression in nonbrain tissues highlight the concept of tissue/region/cell-specific expression of transcripts potentially being determined by disease state and at specific time points in development or ageing. 29 However, our data do not exclude potentially important functional roles for the other transcripts within this locus.…”

Variation at the TRIM11 locus modifies Progressive Supranuclear Palsy phenotype

“…The eQTL profile of our significant SNPs in GTEx, when analysed individually, was particularly interesting. The strong association between several SNPs in high LD with rs564309 and decreasing TRIM11 and TRIM17 expression in non-brain tissues highlight the concept of tissue/region/cell specific expression of transcripts potentially being determined by disease state and at specific time points in development or ageing (29). However, our data does not exclude potentially important functional roles for the other transcripts within this locus.…”

Integration of eQTL and Parkinson’s disease GWAS data implicates 11 disease genes

“…The availability of large transcriptomic datasets and advanced statistical tools and methods to integrate expression platform with GWAS data improves our ability to identify candidate disease-causing genes to investigate further (Dobbyn et al , 2017; Pardiñas et al , 2018). Recent efforts in PD at the 7p15.3 locus have shown the risk variants in GPNMB act as expression QTL (Murthy et al , 2017).…”