Abstract
Purpose :
Genome-wide association studies (GWAS) have identified common and rare variants in association with age-related macular degeneration (AMD). Despite the success of GWAS, the molecular mechanism underlying AMD gene-disease associations, however, is largely unknown. The human proteome plays direct role in biological processes and is major resource for druggable therapeutic targets. In this study, we systematically evaluated the causal influence of plasma proteins on AMD by cross-linking GWAS of plasma proteins with AMD.
Methods :
We curated published GWAS of human plasma proteome which identified cis- and trans- protein quantitative trait loci (pQTLs) for approximately 2600 proteins. cis-pQTLs were defined as the SNPs residing within +/-1Mb of the protein-coding genes, and the other pQTLs were trans. AMD GWAS studies included the International AMD Genomics Consortium (16,144 cases and 17,832 controls), the Boston-French-FINRISK study (4332 cases and 25,268 controls), and the UK Biobank (5860 cases and 126,726 controls). GWAS of proteins and AMD were conducted in independent populations. Two-sample Mendelian randomization (MR) and colocalization analysis were used to infer causal associations between proteins and AMD using pQTLs as instrument variables.
Results :
We identified trans-pQTL hotspots across different chromosomes which harbored causal variants for AMD and multiple proteins, such as genetic loci near CFH (chr.1), C7 (chr.5), CTRB2 (chr.16), and APOE (chr.19). We proposed a remotely regulatory mechanism of AMD showing AMD risk loci regulated distant proteins (trans-proteins) by altering local genes or proteins, which in turn may affect the disease. Gene ontology enrichment analysis suggested that the trans-proteins were enriched for genes involved in response to nutrient (P=0.005) and retina homeostasis (P=0.01). MR and colocalization analysis identified putatively causal pathways for AMD. For example, the APOE loci drive the causal effects of APOE on AMD in cis (Beta=-0.52, PMR=1.5x10-23), and may also through vertical pleiotropic effects on multiple trans-proteins including MAN2B2, NAPB, and LRRN1.
Conclusions :
Our study not only identified novel proteins associated with AMD, but also defined network structures that shed light on the regulatory mechanism of AMD pathogenesis.
This is a 2021 ARVO Annual Meeting abstract.