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

Abstract

Understanding the tissue-specific genetic architecture of protein levels is instrumental to understand the biology of health and disease. 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 (713 CSF, 931 plasma and 1079 brain) in a large and well-characterized cohort. We identified 274, 127 and 32 protein quantitative loci (pQTL) for CSF, plasma and brain respectively. cis-pQTL were more likely to be shared across tissues but trans-pQTL tend to be tissue-specific. Between 44% to 68.2% of the pQTL do not colocalize with expression, splicing, methylation or histone QTLs, indicating that protein levels have a different genetic architecture to those that regulate 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. Here we present the first multi-tissue study yielding hundred of novel pQTLs. This data will be instrumental to identify the functional gene from GWAS signals, identify novel biological protein-protein interactions, identify novel potential biomarkers and drug targets for complex traits.

Genetically independent phenotype analysis identifies LPA and VCAM1 as drug targets for human ageing

“…Importantly, the Mendelian randomisation analysis was restricted to blood pQTL only, which limited our ability to detect causal effects of proteins levels on healthy ageing in other tissues. While it is likely there are proteins with tissue-specific effects on ageing, particularly in the brain, the samples needed for detection of such pQTL are less readily available and therefore more difficult to study at scale (although progress is being made 36 ). However, the blood may be a particularly suitable tissue to identify ageing-related proteins.…”