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. 2023 Feb 11;9(1):24.
doi: 10.1038/s41531-023-00461-9.

A proteogenomic view of Parkinson's disease causality and heterogeneity

Sergio Kaiser #  1 , Luqing Zhang #  2 , Brit Mollenhauer  3 , Jaison Jacob  2   4 , Simonne Longerich  5 , Jorge Del-Aguila  5 , Jacob Marcus  5 , Neha Raghavan  5 , David Stone  6 , Olumide Fagboyegun  6 , Douglas Galasko  7 , Mohammed Dakna  3 , Bilada Bilican  8   9 , Mary Dovlatyan  8 , Anna Kostikova  1 , Jingyao Li  8 , Brant Peterson  8   10 , Michael Rotte  1 , Vinicius Sanz  8 , Tatiana Foroud  11 , Samantha J Hutten  12 , Mark Frasier  12 , Hirotaka Iwaki  13 , Andrew Singleton  13 , Ken Marek  14 , Karen Crawford  15 , Fiona Elwood  8   16 , Mirko Messa  17   18 , Pablo Serrano-Fernandez  19
Affiliations

A proteogenomic view of Parkinson's disease causality and heterogeneity

Sergio Kaiser et al. NPJ Parkinsons Dis. .

Abstract

The pathogenesis and clinical heterogeneity of Parkinson's disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into "endotypes". The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.

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Conflict of interest statement

The authors report no competing interests. A.S. is an editor for npj Parkinson’s Disease. A.S. was not involved in the journal’s review of, or decisions related to, this paper.

Figures

Fig. 1
Fig. 1. Study analytical design.
1103 subjects were analyzed with SomaScan for 4135 unique proteins in CSF. The comparison between GBA + PD patients and GBA + unaffected controls (UC) retrieved six differentially expressed (DE) proteins. The comparison between LRRK2 + PD patients and LRRK2 + UC retrieved seven DE proteins. The comparison between idiopathic PD patients and HC non-mutation carriers retrieved 23 DE proteins. Patients and controls were also combined and compared, which retrieved 122 DE proteins. Idiopathic PD patients were further analyzed, and two endotypes were identified based on CSF proteomics. 1264 subjects were sequenced genome wide to detect a total of 9743041 SNPs. For the 804 patients that had both genomic and proteomic data, a pQTL analysis was performed that identified 744 unique proteins with a significant cis-pQTL. The pQTLs combined with a meta GWAS for PD performed by Nalls et al., led to the proposal of 68 unique CSF proteins presumed to be causal for PD.
Fig. 2
Fig. 2. Causal Analysis.
A Locus visualization of GPNMB pQTL hits suggest a strong association between GPNMB SOMAmer levels and its cis-SNPs. Colors indicate the linkage disequilibrium (LD) correlation of other SNPs with chr7:23294144 (rs858275). B Locus visualization of GWAS hits in the GPNMB locus for the risk of developing PD. The y-axis is the −log10 nominal p value of the GWAS results.
Fig. 3
Fig. 3. Idiopathic PD endotypes.
A Heatmap of z-scores of the protein values as measured with SomaScan, corresponding to the two modules identified using Weighted Gene Co-expression Network Analysis (WGCNA). The proteins in these modules are used for cluster analysis using Consensus Clustering, which retrieves two clusters (endotypes) of idiopathic PD patients. Patients are shown in the x-axis, separated by endotype, while proteins are shown in the y-axis, separated by module. B Tracking plot depicting how the idiopathic PD patients are assigned to specific endotypes by Consensus Clustering as the number of potential endotypes increases. C Partition tree predicting endotype membership of the idiopathic PD patients based on clinical variables only. One node suffices to separate patients into endotypes based on phospho-tau levels (p-tau) in CSF as measured with a clinical assay, the cut-off being 11 pg/mL.
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