Mapping the serum proteome to neurological diseases using whole genome sequencing

Abstract

Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer’s disease, GPNMB and Parkinson’s disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.

Technical Performance Evaluation of Olink Proximity Extension Assay for Blood-Based Biomarker Discovery in Longitudinal Studies of Alzheimer's Disease

“…A smaller cohort of Hong Kong Chinese ( n = 180) found 429 differentially abundant proteins in AD plasma (out of 1,160 tested), which included AXIN1 and uPA ( 16 ). In a large study of protein quantitative trait loci and Olink quantified serum proteomes in 2,893 individuals, CD33 protein was causally linked to AD disease traits ( 17 ). While AXIN, uPA, OSM and MMP9 may be emerging as potential biomarker targets, their performance and specificity is not yet well understood across multiple populations and neurological diseases.…”

Gene-based whole genome sequencing meta-analysis of 250 circulating proteins in three isolated European populations

“…We use a significance threshold of 7.45 × 10 −11 , which we derived by computing the effective number of traits and variants analysed [ 11 , 38 ]. Thresholds obtained by permutation testing for rare variant tests in the UK Biobank, on a higher number of both variants and traits, are markedly greater (2 × 10 −9 ) [ 39 ], suggesting that the threshold used in this study is conservative.…”

From genome to phenome via the proteome: broad capture, antibody-based proteomics to explore disease mechanisms

“…A total of 256 (16.5%) credible sets contained cis-pQTLs not previously reported, including 131 proteins that have not been measured by previous platforms (Fig. 1B) (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Notably 125 signals were for 101 previously targeted proteins, the majority of which (n=92 proteins) have been targeted using non-antibody-based technologies in samples sizes up to 30 times larger than ours (10,11,15,16) (Fig.…”

“…Despite recent advances and early successes, the field is still in its infancy with respect to the scale and protein capture, with existing broad-capture technologies currently targeting less than a third of all proteins encoded in the human genome (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), not capturing posttranslational modifications, or providing absolute protein quantification.…”

“…The development of broad-capture proteomic assays, targeting thousands of proteins in parallel, now enables proteogenomic approaches which can efficiently identify causal genes by systematically testing for shared genetic regulation of protein levels or function and disease susceptibility. This has catalyzed substantial advances in the identification of a) causal genes and proteins underlying established disease 'loci', and b) molecular 'hubs' that connect the genome not to one but many diseases through the encoded protein (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Previous large-scale proteogenomic studies covering thousands of proteins have almost exclusively used aptamerbased assays (10,11,15,16).…”