Chengran C. Yang, United States of America
Washington University in St. Louis PsychiatryAuthor Of 3 Presentations
INTEGRATIVE MULTI-TISSUE MULTI-OMICS FOR BIOMARKER AND THERAPEUTIC TARGET DISCOVERY IN ALZHEIMER DISEASE (AD) AND PARKINSON DISEASE (PD)
Abstract
Aims
To identify causal pathway of AD and PD risk and drug targets by generating and analyzing multi-tissue proteomic and genetic data from a large cohort.
Methods
We generated a genomic atlas of protein levels in multiple neurologically relevant tissues (380 brain, 835 cerebrospinal fluid (CSF) and 529 plasma), by profiling thousands of proteins in a large and well-characterized cohort. We used Mendelian Randomization (MR) and colocalization methods to identify proteins in the causal pathway of two neurological diseases and drug targets for repurposing.
Results
Combining both MR and colocalization results, we found that one CSF, 13 plasma and six brain proteins were likely to be in the causal pathways for AD risk. Among these proteins, plasma CD33 was a risk factor towards AD and had been used as a drug target for other diseases, such as prostate cancer. As for PD risk, 13 CSF, 12 plasma and 23 brain proteins were likely to be the cause. Among these proteins, plasma IDUA was prioritized as it was encoded by a risk locus for PD and as a drug target for chondroitin sulfate, reported to treat osteoarthritis. IDUA is required for the lysosomal degradation of glycosaminoglycans, dermatan sulfate and heparan sulfate.
Conclusions
Our results prioritized several proteins likely to be in the causal pathways leading to AD and PD risk. These nominated proteins can facilitate mapping the disease GWAS results into biological mechanisms, and further leading to precision medicine in neurological and/or psychiatric traits.
LIVE DISCUSSION
MULTI-TISSUE PROTEOMIC SIGNATURES OF GENETICALLY-DEFINED ALZHEIMER DISEASE CASES: A WINDOW INTO PRECISION MEDICINE
Abstract
Aims
We and others recently identified several Alzheimer disease (AD) risk variants in TREM2. Here we aim to elucidate the downstream effect of genes and functional mechanisms leading to AD through multi-tissue proteomics study of AD, autosomal-dominant AD (ADAD) and TREM2 risk variant carriers.
Methods
Deep proteomics profiling was obtained (SOMAscan; 1305 proteins) from brain, cerebrospinal fluid (CSF), and plasma tissue. These neurologically relevant tissues were from Knight-ADRC and DIAN cohorts with comprehensive clinical information about AD pathology and cognition. After stringent QC, we analyzed 1079 proteins in brain (n=370), 713 proteins in CSF (n=699), and 931 proteins in plasma (n=486).
Results
We identified 27, 38 and 69 TREM2-specific proteins in brain, CSF, and plasma, respectively (at Bonferroni-corrected significance). Twenty-three plasma proteins showed nominal differential levels in brain and CSF and led to a prediction model, which discriminates TREM2 carriers from controls (AUC=0.94) and other AD cases (AUC=0.91) well. We identified 371 ADAD-specific proteins, among which 225 were nominally associated with AD neuropath traits. Furthermore, 54, 89, and 85 proteins showed nominal differential levels in sporadic AD vs controls in brain, CSF, and plasma. TREM2-specific proteins are involved in growth factors including VEGF, PDGF, EGF and immunological response. ADAD-specific proteins converge in immunological response pathways including cytokine-mediated signaling and DAP12-mediated pathway.
Conclusions
Our multi-tissue proteomics study for genetically defined AD cases identified multiple novel AD biomarker candidates. These findings not only help create novel prediction models but also point to specific pathways implicated in AD, supporting its potential utility as a clinically useful biomarker.
Presenter of 2 Presentations
INTEGRATIVE MULTI-TISSUE MULTI-OMICS FOR BIOMARKER AND THERAPEUTIC TARGET DISCOVERY IN ALZHEIMER DISEASE (AD) AND PARKINSON DISEASE (PD)
Abstract
Aims
To identify causal pathway of AD and PD risk and drug targets by generating and analyzing multi-tissue proteomic and genetic data from a large cohort.
Methods
We generated a genomic atlas of protein levels in multiple neurologically relevant tissues (380 brain, 835 cerebrospinal fluid (CSF) and 529 plasma), by profiling thousands of proteins in a large and well-characterized cohort. We used Mendelian Randomization (MR) and colocalization methods to identify proteins in the causal pathway of two neurological diseases and drug targets for repurposing.
Results
Combining both MR and colocalization results, we found that one CSF, 13 plasma and six brain proteins were likely to be in the causal pathways for AD risk. Among these proteins, plasma CD33 was a risk factor towards AD and had been used as a drug target for other diseases, such as prostate cancer. As for PD risk, 13 CSF, 12 plasma and 23 brain proteins were likely to be the cause. Among these proteins, plasma IDUA was prioritized as it was encoded by a risk locus for PD and as a drug target for chondroitin sulfate, reported to treat osteoarthritis. IDUA is required for the lysosomal degradation of glycosaminoglycans, dermatan sulfate and heparan sulfate.
Conclusions
Our results prioritized several proteins likely to be in the causal pathways leading to AD and PD risk. These nominated proteins can facilitate mapping the disease GWAS results into biological mechanisms, and further leading to precision medicine in neurological and/or psychiatric traits.
LIVE DISCUSSION