Biology subjects

Venkataraman, G. R.

Publications and source records attributed to Venkataraman, G. R..

6 recordsLinked to original sources

bioRxiv2024

Identification of Novel Biomarkers for Alzheimer's Disease and Related Dementias Using Unbiased Plasma Proteomics

Alzheimers disease (AD) and related dementias (ADRD) is a complex disease with multiple pathophysiological drivers that determine clinical symptomology and disease progression. These diseases develop insidiously over time, through many pathways and disease mechanisms and continue to have a huge societal impact for affected individuals and their families. While emerging blood-based biomarkers, such as plasma p-tau181 and p-tau217, accurately detect Alzheimer neuropthology and are associated with faster cognitive decline, the full extension of plasma proteomic changes in ADRD remains unknown. Earlier detection and better classification of the different subtypes may provide opportunities for earlier, more targeted interventions, and perhaps a higher likelihood of successful therapeutic development. In this study, we aim to leverage unbiased mass spectrometry proteomics to identify novel, blood-based biomarkers associated with cognitive decline. 1,786 plasma samples from 1,005 patients were collected over 12 years from partcipants in the Massachusetts Alzheimers Disease Research Center Longitudinal Cohort Study. Patient metadata includes demographics, final diagnoses, and clinical dementia rating (CDR) scores taken concurrently. The ProteographTM Product Suite (Seer, Inc.) and liquid-chromatography mass-spectrometry (LC-MS) analysis were used to process the plasma samples in this cohort and generate unbiased proteomics data. Data-independent acquisition (DIA) mass spectrometry results yielded 36,259 peptides and 4,007 protein groups. Linear mixed effects models revealed 138 differentially abundant proteins between AD and healthy controls. Machine learning classification models for AD diagnosis identified potential candidate biomarkers including MBP, BGLAP, and APoD. Cox regression models were created to determine the association of proteins with disease progression and suggest CLNS1A, CRISPLD2, and GOLPH3 as targets of further investigation as potential biomarkers. The Proteograph workflow provided deep, unbiased coverage of the plasma proteome at a speed that enabled a cohort study of almost 1,800 samples, which is the largest, deep, unbiased proteomics study of ADRD conducted to date.

neuroscience↗

bioRxiv2023

Nanoparticle Enrichment Mass-Spectrometry Proteomics Identifies Protein Altering Variants for Precise pQTL Mapping

Genome-wide association studies (GWAS) with proteomics generate hypotheses on protein function and offer genetic evidence for drug target prioritization. Although most protein quantitative loci (pQTLs) have so far been identified by high-throughput affinity proteomics platforms, these methods also have some limitations, such as uncertainty about target identity, non-specific binding of aptamers, and inability to handle epitope-modifying variants that affect affinity binding. Mass spectrometry (MS) proteomics has the potential to overcome these challenges and broaden the scope of pQTL studies. Here, we employ the recently developed MS-based Proteograph workflow (Seer, Inc.) to quantify over 18,000 unique peptides from almost 3,000 proteins in more than 320 blood samples from a multi-ethnic cohort. We implement a bottom-up MS-proteomics approach for the detection and quantification of blood-circulating proteins in the presence of protein altering variants (PAVs). We identify 184 PAVs located in 137 genes that are significantly associated with their corresponding variant peptides in MS data (MS-PAVs). Half of these MS-PAVs (94) overlap with cis-pQTLs previously identified by affinity proteomics pQTL studies, thus confirming the target specificity of the affinity binders. An additional 54 MS-PAVs overlap with trans-pQTLs (and not cis-pQTLs) in affinity proteomics studies, thus identifying the putatively causal cis-encoded protein and providing experimental evidence for its presence in blood. The remaining 36 MS-PAVs have not been previously reported and include proteins that may be inaccessible to affinity proteomics, such as a variant in the incretin pro-peptide (GIP) that associates with type 2 diabetes and cardiovascular disease. Overall, our study introduces a novel approach for analyzing MS-based proteomics data within the GWAS context, provides new insights relevant to genetics-based drug discovery, and highlights the potential of MS-proteomics technologies when applied at population scale. HighlightsO_LIThis is the first pQTL study that uses the Proteograph (Seer Inc.) mass spectrometry-based proteomics workflow. C_LIO_LIWe introduce a novel bottom-up proteomics approach that accounts for protein altering variants in the detection of pQTLs. C_LIO_LIWe confirm the target and potential epitope effects of affinity binders for cis-pQTLs from affinity proteomics studies. C_LIO_LIWe establish putatively causal proteins for known affinity proteomics trans-pQTLs and confirm their presence in blood. C_LIO_LIWe identify novel protein altering variants in proteins of clinical relevance that may not be accessible to affinity proteomics. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/537640v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@5db14forg.highwire.dtl.DTLVardef@123c1edorg.highwire.dtl.DTLVardef@90ebb6org.highwire.dtl.DTLVardef@6320ff_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2021

Bayesian mixture model for clustering rare-variant effects in human genetic studies

Rare-variant aggregate analysis from exome and whole genome sequencing data typically summarizes with a single statistic the signal for a gene or the unit that is being aggregated. However, when doing so, the effect profile within the unit may not be easily characterized across one or multiple phenotypes. Here, we present an approach we call Multiple Rarevariants and Phenotypes Mixture Model (MRPMM), which clusters rare variants into groups based on their effects on the multivariate phenotype and makes statistical inferences about the properties of the underlying mixture of genetic effects. Using summary statistic data from a meta-analysis of exome sequencing data of 184,698 individuals in the UK Biobank across 6 populations, we demonstrate that our mixture model can identify clusters of variants responsible for significantly disparate effects across a multivariate phenotype; we study three lipid and three renal traits separately. The method is able to estimate (1) the proportion of non-null variants, (2) whether variants with the same predicted consequence in one gene behave similarly, (3) whether variants across genes share effect profiles across the multivariate phenotype, and (4) whether different annotations differ in the magnitude of their effects. As rare-variant data and aggregation techniques become more common, this method can be used to ascribe further meaning to association results.

genetics↗

bioRxiv2020

Pervasive additive and non-additive effects within the HLA region contribute to disease risk in the UK Biobank

The human leukocyte antigen (HLA) region is one of the most disease-associated regions of the human genome, yet even well-studied alleles in the HLA region have unknown impact on disease. Here, we study the effect of 156 HLA alleles on 677 binary phenotypes for 337,138 individuals in the UK Biobank. We assess HLA allele associations and subsequently use Bayesian Model Averaging for conditional analysis, a) replicating 88 known associations between HLA alleles and binary disease phenotypes such as cancer, and b) discovering 90 novel associations to phenotypes such as skin and reproductive tract cancers and to other phenotypes not previously associated with the HLA region (e.g. anemias and acne). We find several non-additive effects, suggesting a more complex landscape of disease-modifying effects throughout the region. Finally, we discover associations between homozygous HLA allele burden and several cancer and other phenotypes, suggesting that peptide presentation spectra as coded for by the HLA region are important in determining disease risk. Our results demonstrate the HLA regions complexity and richness while underscoring its clinical relevance.

genetics↗

bioRxiv2019

Genetics of 38 blood and urine biomarkers in the UK Biobank

Clinical laboratory tests are a critical component of the continuum of care and provide a means for rapid diagnosis and monitoring of chronic disease. In this study, we systematically evaluated the genetic basis of 38 blood and urine laboratory tests measured in 358,072 participants in the UK Biobank and identified 1,857 independent loci associated with at least one laboratory test, including 488 large-effect protein truncating, missense, and copy-number variants. We tested these loci for enrichment in specific single cell types in kidney, liver, and pancreas relevant to disease aetiology. We then causally linked the biomarkers to medically relevant phenotypes through genetic correlation and Mendelian randomization. Finally, we developed polygenic risk scores (PRS) for each biomarker and built multi-PRS models using all 38 PRSs simultaneously. We found substantially improved prediction of incidence in FinnGen (n=135,500) with the multi-PRS relative to single-disease PRSs for renal failure, myocardial infarction, liver fat percentage, and alcoholic cirrhosis. Together, our results show the genetic basis of these biomarkers, which tissues contribute to the biomarker function, the causal influences of the biomarkers, and how we can use this to predict disease.

genetics↗

bioRxiv2018

Deep learning facilitates rapid cohort identification using human and veterinary clinical narratives

ObjectiveCurrently, dedicated tagging staff spend considerable effort assigning clinical codes to patient summaries for public health purposes, and machine-learning automated tagging is bottlenecked by availability of electronic medical records. Veterinary medical records, a largely untapped data source that could benefit both human and non-human patients, could fill the gap. Materials and MethodsIn this retrospective study, we trained long short-term memory (LSTM) recurrent neural networks (RNNs) on 52,722 human and 89,591 veterinary records. We established relevant baselines by training Decision Trees (DT) and Random Forests (RF) on the same data. We finally investigated the effect of merging data across clinical settings and probed model portability. ResultsWe show that the LSTM-RNNs accurately classify veterinary/human text narratives into top-level categories with an average weighted macro F1, score of 0.735/0.675 respectively. The evaluation metric for the LSTM was 7 and 8% higher than that of the DT and RF models respectively. We generally did not find evidence of model portability albeit moderate performance increases in select categories. DiscussionWe see a strong positive correlation between number of training samples and classification performance, which is promising for future efforts. The use of LSTM-RNN models represents a scalable structure that could prove useful in cohort selection, which could in turn better address emerging public health concerns. ConclusionDigitization of human and veterinary health information will continue to be a reality. Our approach is a step forward for these two domains to learn from, and inform, one another.

epidemiology↗