Proteogenomic origins of disease in British South Asians

Proteogenomic studies have transformed the way we derive novel insights into human biology and pathophysiology but are currently limited by their proteomic coverage and ancestral representation. Here, we integrate rare and common genetic variation with measurements of >11,000 plasma proteins on two affinity-based platforms (>6,000 targets not previously covered) in 1,535 individuals of British Bangladeshi and Pakistani ancestry of the Genes & Health cohort. We report 3,826 high-confidence common (minor allele frequency (MAF)>1.0%) protein quantitative trait loci (pQTLs), over half of which are novel and including >200 pQTLs with greater MAF in South Asians. Systematic analyses of rare (MAF<1.0%) exonic variants identify 230 gene-protein pairs and highlight the joint and distinct contributions of rare and common variants to inherited differences in protein levels. We expand analyses beyond the nuclear genome and identify 3 mitochondrial pQTLs, including a common variant in MT-RNR1, associated with lower myelin protein zero (MPZ), identifying a potential novel mechanistic link for MT-RNR1s poorly understood role in hearing loss. We create the first proteogenomic disease network in individuals of South Asian ancestry based on 384 cis-pQTL with a shared genetic disease or risk factor signal, including conditions substantially more common in South Asians, such as metabolic diseases or pregnancy-related conditions, providing insights into the underlying mechanisms. In summary, our study demonstrates the value and scientific efficiency of proteomic studies in genetically informative and understudied populations for identifying novel causes of globally relevant diseases.