Objective: To determine whether Parkinson’s disease (PD) risk genotypes at the GPNMB locus associate with distribution of Lewy pathology in brain samples from a spectrum of neurodegenerative diseases.

Background: The single nucleotide polymorphism (SNP) rs199347 in the GPNMB locus has been implicated in risk for PD by genomewide association (1). rs199347 is a non-coding SNP linked to expression of GPNMB in brain tissue and biofluids, where the PD risk allele is associated with elevated GPNMB (2,3). We previously showed that the encoded protein, glycoprotein nonmetastatic melanoma B (GPNMB) interacts with fibrillar alpha-synuclein (aSyn), the protein that accumulates in the hallmark Lewy pathology of PD. Moreover, GPNMB is necessary and sufficient for uptake of aSyn fibrils, and knockout of GPNMB rescues neurons from developing aSyn pathology (2). Thus, we hypothesize that GPNMB expression levels, or SNPs associating with its expression, impact the extent to which aSyn pathology can spread in the brain.

Method: We genotyped rs199347 in 1675 postmortem cases from the Center for Neurodegenerative Disease Research brain bank at the University of Pennsylvania. The cohort included 344 individuals with a primary neuropathological diagnosis (NPDx1) of Lewy body disease (LBD), 626 with NPDx1 of Alzheimer’s disease, and 705 individuals with other neuropathological diagnoses. We evaluated whether rs199347 genotype correlated with spread of various pathologies within this global cohort: specifically, we asked whether genotypes associated with the extent of Aβ (Thal amyloid phase), tau (Braak tau stage), and aSyn (McKeith criteria stage) pathology (4–6). We asked whether rs199347 genotypes predicted pathological stage in additive linear regression models adjusted for sex and age at death.

Results: rs199347 genotype associated with extent of aSyn pathology (p=0.011), but not Aβ (p=0.727) or tau (p=0.115) pathology in our global neurodegenerative disease cohort. For each additional PD risk allele at rs199347, there was a 0.127 increase in McKeith stage, signifying more widespread Lewy pathology. Among the 344 LBD individuals, rs199347 did not predict McKeith stage.

Conclusion: Genotypes at rs199347 in the GPNMB locus associate with extent of aSyn pathology, with more widespread Lewy pathology observed in carriers of PD risk alleles. Our data support a role for GPNMB in transmission of pathological aSyn within human brain.

References: 1. Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2019 Dec;18(12):1091–102.
2. Diaz-Ortiz ME, Seo Y, Posavi M, Carceles Cordon M, Clark E, Jain N, et al. GPNMB confers risk for Parkinson’s disease through interaction with α-synuclein. Science. 2022 Aug 19;377(6608):eabk0637.
3. UKBEC, IPDGC, Murthy MN, Blauwendraat C, Guelfi S, Hardy J, et al. 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):121–33.
4. McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017 Jul 4;89(1):88–100.
5. Thal DR, Rüb U, Orantes M, Braak H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology. 2002 Jun 25;58(12):1791–800.
6. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol (Berl). 2006 Oct;112(4):389–404.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-disease-risk-genotypes-at-the-gpnmb-locus-associate-with-extent-of-post-mortem-lewy-pathology/