Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits

Abstract

Expression quantitative trait loci (eQTL) mapping has successfully resolved some genome-wide association study (GWAS) loci for complex traits. However, there is a need for implementing additional "omic" approaches to untangle additional loci and provide a biological context for GWAS signals. We generated a detailed landscape of the genomic architecture of protein levels in multiple neurologically relevant tissues (brain, cerebrospinal fluid (CSF) and plasma), by profiling thousands of proteins in a large and well-characterized cohort. We identified 274, 127 and 32 protein quantitative loci (pQTL) for CSF, plasma and brain respectively. We demonstrated that cis-pQTL are more likely to be shared across tissues but trans-pQTL are tissue-specific. Between 78% to 87% of pQTL are not eQTL, indicating that protein levels have a different genetic architecture than gene expression. By combining our pQTL with Mendelian Randomization approaches we identified potential novel biomarkers and drug targets for neurodegenerative diseases including Alzheimer disease and frontotemporal dementia. In the context of personalized medicine, these results highlight the need for implementing additional functional genomic approaches beyond gene expression in order to understand the biology of complex traits, and to identify novel biomarkers and potential drug targets for those traits.

Large-Scale Deep Multi-Layer Analysis of Alzheimer’s Disease Brain Reveals Strong Proteomic Disease-Related Changes Not Observed at the RNA Level

“…Indeed, we have recently shown that SMOC1 is strongly elevated in AD cerebrospinal fluid (CSF) 26,40,47 . Consistent with our mod-QTL findings, levels of SMOC1 in CSF were recently identified to be influenced by a pQTL associated with the APOE4 genotype 48 .…”

A trans‐omic Mendelian randomization study of parental lifespan uncovers novel aging biology and therapeutic candidates for chronic diseases

“…In light of recent investigations reporting that the majority of eQTLs do not necessarily influence protein levels (He et al, 2020;Yang et al, 2020) we used MR to identify key eProteins, and eMetabolites, that may influence human lifespan. In order to discover the role of these genetically regulated traits in human homeostasis while at the same time determining whether they could be effectively and safely targeted to promote healthy aging and human longevity, we report MR findings across the human disease-related phenome.…”

Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease

“…The levels of α-Syn were measured in CSF, plasma, and brain (parietal cortex) using an aptamer-based approach (SOMAScan platform) [70]. After stringent quality control, CSF (n = 835), plasma (n = 529), and brain (n = 380) samples were included in the downstream analyses (Additional file 2: Table S2).…”