Category: Parkinson's Disease: Non-Motor Symptoms
Objective: Analyze multi-omics data from the PPMI cohort to identify molecular markers associated with self-reported gastrointestinal (GI) dysfunction in Parkinson’s disease (PD) patients.
Background: PD is a multi-system disease with a long prodromal phase featured by non-motor symptoms, including GI problems. Up to date, the molecular changes linked to GI dysfunctions remain unknown.
Method: We conducted longitudinal clustering to delineate trajectories of GI severity over five years using a k-means algorithm and CopyMean imputation in kml [1] and the SCOPA-AUT questionnaire and summing up the scales of Q1-7 as the GI severity from 1260 PD cases. Of the PD with genomics data, we classified high (n = 401) and low (n = 462) based on a cut-off point of distinguishing PD and control and performed a logistic regression including 5.9 million genetic variants (> 5% minor allele frequency) and covariates (sex, age at baseline, and disease duration) using PLINK2.0 [2]. We curated cerebrospinal fluid and urine proteomics, plasma metabolomics using limma [3], and blood transcriptome associated with high GI severity using DESeq2 [4]. We used an ordinal linear logistic regression to test the association of GI severity with UPDRS and MoCA assessments and linear regression to test the association with caudate thickness volume.
Results: We identified two clusters with different trajectories of GI progression (p = 0.0003, fig 1). The cluster with a high GI score has a higher proportion of LRRK2 carriers (p = 0.033), longer disease duration (p = 0.005), and older age at baseline (p = 0.0004). We identified a common variant in chromosome 10 associated with increased severity of GI symptoms (OR = 1.76; p = 9.5×10-8, fig 2). Individuals with elevated GI scores showed lower levels of PE, GalCer, and a-tocopherol metabolites (fig 3a) and down-regulation of IFI27, EREG, USP18, CCL2 and CCL8 transcripts (fig 3b). The high GI score is correlated with increased UPDRS-III (p = 0.06) and lower MoCA scores (p = 4.95×10-6), and higher CSF p-tau (p = 0.02) and a-beta levels (p = 0.01).
Conclusion: We uncovered genetic variations, metabolites, and genes associated with self-reported GI symptoms in PD patients. The progression of GI dysfunction aligns with motor and cognitive impairments. The integrative multi-omics approach uncovers novel molecular markers in PD patients with severe GI symptoms.
References: Genolini, C., Alacoque, X., Sentenac, M., & Arnaud, C. (2015). kml and kml3d: R packages to cluster longitudinal data. Journal of statistical software, 65, 1-34.
Chang, C. C., Chow, C. C., Tellier, L. C., Vattikuti, S., Purcell, S. M., & Lee, J. J. (2015). Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience, 4(1), s13742-015.
Ritchie, M. E., Phipson, B., Wu, D. I., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015). limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic acids research, 43(7), e47-e47.
Love, M. I., Huber, W., & Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology, 15, 1-21.
To cite this abstract in AMA style:
M. Lai, S. Kulkarni, B. Benitez. Molecular Landscape of Gastrointestinal Dysfunctions in Parkinson’s Disease [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/molecular-landscape-of-gastrointestinal-dysfunctions-in-parkinsons-disease/. Accessed October 12, 2024.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/molecular-landscape-of-gastrointestinal-dysfunctions-in-parkinsons-disease/