Objective: To conduct a genome-wide association study (GWAS) of striatal [I¹²³]-FP-CIT SPECT signal as endophenotype to explore possible associations between genetic background and nigrostriatal dopaminergic depletion in Parkinson’s disease (PD).

Background: Previous candidate gene studies have revealed associations between specific single nucleotide polymorphisms (SNPs) in dopamine-related genes and striatal [I¹²³]-FP-CIT SPECT signal PD. Exploratory GWAS analysis may provide further insight into the genetic influences on nigrostriatal dopamine depletion as measured by [I¹²³]-FP-CIT SPECT in PD.

Method: We included 360 de novo PD patients from the Parkinson Progression Markers Initiative (PPMI) consortium. We analyzed [I¹²³]-FP-CIT SPECT images and Illumina NeuroX array genotyping data. We used Specific Binding Ratios (SBR) from PPMI pipeline, which represent the uptake of the Dopamine Transporter (DAT) in putamen and caudate. We performed quality control on the GWAS data, and, after filtering, a total of 48,572 SNPs remained for further analysis. GWAS linear regression analyses were calculated and included additive, recessive, and dominant models, controlled for age, sex, the first two Principal Components of PD patients’ genetic data to control for population structure. Multiple comparisons were corrected using the False Discovery Rate (FDR).

Results: In PD patients, we found statistically significant (p(FDR)<0.05) associations in recessive lineal models between putaminal DAT signal and a total of 27 SNPs, including 15 SNPs that could be linked to 17 different genes. All beta values obtained in these recessive models were positive, suggesting a protective effect of the minor allele against putaminal dopaminergic depletion (Table 1).

Conclusion: Using the first exploratory GWAS study with [I¹²³]-FP-CIT SPECT imaging endophenotypes to date, we identified and annotated 15 genetic variants that showed significant associations with putaminal DAT uptake in PD patients. These variants are related to less reduction in putaminal DAT uptake, reflecting a possible protective action. Several of the implicated genes have previously been associated with PD or neuroprotective pathways in general, including SNCA, SLC12A8, NQO2, and UPK1A.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-polymorphisms-associated-with-nigrostriatal-dopaminergic-depletion-as-measured-with-i123-fp-cit-spect-in-parkinsons-disease/