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. 2017 Jul;18(3):121-133.
doi: 10.1007/s10048-017-0514-8. Epub 2017 Apr 8.

Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson's disease on chromosome 7p15.3

Megha N Murthy  1   2 , Cornelis Blauwendraat  3 ; UKBEC; Sebastian Guelfi  4 ; IPDGC; John Hardy  4 , Patrick A Lewis  2   4 , Daniah Trabzuni  5   6
Affiliations

Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson's disease on chromosome 7p15.3

Megha N Murthy et al. Neurogenetics. 2017 Jul.

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.

Keywords: Antisense and non-coding RNA; Chr7 locus (GPNMB); Human brain expression QTLs; Parkinson’s disease (PD); Risk SNP rs199347.

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Conflict of interest statement

Funding

The Braineac project was supported by the MRC through the MRC Sudden Death Brain Bank Grant (MR/G0901254) to J.H. P.A.L. was supported by the MRC (grants MR/N026004/1 and MR/L010933/1) and Michael J. Fox Foundation for Parkinson’s Research. D.T. was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia, and the Michael J. Fox Foundation for Parkinson’s Research and MRC grant (MR/N026004/1). M.M. was funded by the DST INSPIRE Fellowship (IF120351), DST India, and the Newton Bhabha Fund by the British Council and DBT India. We acknowledge support from the National Institute for Health Research (NIHR) Biomedical Research Centre.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Figures

Fig. 1
Fig. 1
Regional association plot for rs199347 SNP at Chr7p15.3 locus from discovery phase. The plot shows regions ±1 Mb most significant SNP from PD GWAS study and the five transcripts in the locus investigated in this study. This locus was named as GPNMB locus. Only the five transcripts at this locus are shown in this figure. Figure modified from Nalls et al. [3]
Fig. 2
Fig. 2
Genomic location of the Chr7p15.3 locus representing the five transcripts and SNP rs199347. The figure represents the genomic location of the genes in the Chr7p15.3 locus, namely, GPNMB, KLHL7, KLHL7-AS1, NUPL2, and AC005082.12 along with their different isoforms. The position of rs199347 (intron 2–3 of GPNMB) is also represented. The GRCh37 build was used to construct the genomic location in this figure
Fig. 3
Fig. 3
Regional distribution of mRNA expression patterns of the three transcripts (GPNMB, KLHL7, and NUPL2) in Chr7p15.3 locus in Braineac. A Box plot of mRNA expression levels for GPNMB in 10 brain regions, from microarray experiments on a log2 scale (y axis). CRBL cerebellum, OCTX occipital cortex, FCTX frontal cortex, TCTX temporal cortex, SNIG substantia nigra, WHMT white matter, HIPP hippocampus, PUTM putamen, THAL thalamus, MEDU medulla. This plot shows that GPNMB expression in TCTX is higher by 2.4-fold change (FC) compared with CRBL. B Box plot of mRNA expression levels for KLHL7 in 10 brain regions, from microarray experiments on a log2 scale (y axis). This plot shows that KLHL7 expression in CRBL is higher by 1.5 FC compared with WHMT. C Box plot of mRNA expression levels for NUPL2 in 10 brain regions, from microarray experiments on a log2 scale (y axis). This plot shows that NUPL2 expression in TCTX is higher by 1.2 FC compared with SNIG. Whiskers extend from the box to 1.5 times the inter-quartile range. Whiskers extend from the box to 1.5 times the inter-quartile range
Fig. 4
Fig. 4
The effect of rs199347 on the expression levels of transcripts (GPNMB, KLHL7, and NUPL2) in Chr7p15.3 locus in Braineac. A Box plot shows GPNMB expression stratified by rs199347 in 134 brain samples. Increased expression was associated with the homozygous major allele (AA) in TCTX, FCTX, OCTX, HIPP, CRBL, and PUTM. A similar pattern was observed in other brain regions, but not as significantly. B Box plot shows KLHL7 expression stratified by rs199347 in 134 brain samples. No significant association was observed after multiple testing correction FDR was applied. C Box plot shows NUPL2 expression stratified by rs199347 in 134 brain samples. The SNP is associated with increased expression in CRBL, TCTX, and FCTX, although no significant association was observed after multiple testing correction FDR was applied. Whiskers extend from the box to 1.5 times the inter-quartile range
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