Neurological Biomarkers: How Whole Genome Sequencing Maps the Serum Proteome

The complexity of neurological disorders, compounded by their rising global burden, underscores the urgent need for innovative diagnostic and therapeutic approaches. This study, published in Nature Communications, pioneers a novel approach by integrating whole genome sequencing (WGS) with protein quantitative trait locus (pQTL) analysis to decode the serum proteome and its links to neurological diseases. By examining 184 neurologically relevant proteins across two isolated Greek population cohorts (MANOLIS and Pomak), this research offers transformative insights into protein-disease associations, with implications for biomarker discovery and drug repurposing.

The Study Design: Merging Genomics and Proteomics
Proteins are fundamental to disease pathogenesis and serve as accessible biomarkers for diagnostics and drug targets. This study employs WGS to capture a comprehensive spectrum of genetic variations in nearly 3,000 individuals. Using Olink’s proximity extension assay (PEA) technology, the research quantified serum protein levels to identify 214 independent genetic variants linked to 107 proteins, including 114 novel variants. This dual-cohort approach ensures robust meta-analysis while leveraging the unique genetic characteristics of isolated populations.

Key Findings: Protein-Disease Associations
The study's findings illuminate the genetic underpinnings of the serum proteome and its relationship to neurological diseases. Notably:
Alzheimer’s Disease (AD) and CD33:
A strong causal link was identified between serum levels of CD33, a myeloid cell surface antigen, and AD. The cis-pQTL regulating CD33 expression colocalized with known AD-associated loci, suggesting transcriptional regulation as a shared mechanism in the brain and blood. This highlights CD33 as a potential biomarker for early AD diagnosis.

Parkinson’s Disease (PD) and GPNMB:
The study identified a cis-pQTL associated with decreased serum levels of GPNMB, a protein linked to lysosomal dysfunction in PD. The findings support the utility of GPNMB as a non-invasive biomarker, enhancing the translational potential of serum-based diagnostics for PD.

Schizophrenia and MSR1:
Serum levels of MSR1, a macrophage scavenger receptor, were causally linked to schizophrenia. MSR1's role in immune modulation and its regulation by variants in transcriptional regulatory regions underscores its significance in neuroinflammatory pathways implicated in schizophrenia.

Heritability and Genetic Architecture
The research revealed a median heritability of 33.3% for the serum proteins studied, with some proteins, such as CD33 and GPNMB, exhibiting heritability exceeding 80%. This underscores the genetic contribution to serum protein variability and its translational relevance. Additionally, the study distinguished cis-acting pQTLs, regulating protein expression locally, from trans-acting pQTLs, which influence expression through distal mechanisms.

Clinical Implications: Biomarkers and Drug Repurposing
The study's integration of pQTL data with Mendelian randomization and colocalization analyses identified numerous proteins as potential drug targets. For instance:

CD33: Anti-CD33 drugs, already used in leukemia treatment, hold promise for AD therapy.
DPEP1: Identified as a biomarker for osteoarthritis and multisite chronic pain, with potential repurposing of cilastatin, a DPEP1 inhibitor, for pain management.

Limitations and Future Directions
While groundbreaking, the study acknowledges limitations, including its focus on European ancestry populations and serum proteome. Expanding such analyses to diverse populations and tissues, such as cerebrospinal fluid, could further enhance biomarker discovery. Moreover, integrating orthogonal validation methods, like epitope-independent assays, would address potential biases in protein quantification.

Conclusion
This study exemplifies the potential of integrating genomics and proteomics to unravel the molecular basis of neurological diseases. By identifying causal protein-disease associations and highlighting drug repurposing opportunities, it sets the stage for precision medicine approaches tailored to neurological conditions. The findings not only advance our understanding of disease pathways but also provide a valuable resource for future research into brain-related disorders.

References:
Png, G., Barysenka, A., Repetto, L. et al. Mapping the serum proteome to neurological diseases using whole genome sequencing. Nat Commun 12, 7042 (2021).