Pulmonary arterial hypertension (PAH) is a rare, fatal condition characterized by the gradual occlusion of the pulmonary arterioles leading to progressively increased pulmonary vascular resistance with worsening right heart failure and death. While rare mutations (e.g., in BMPR2) have been reported in a minority of patients, most patients carry no established mutations. We recently published on common genetic variation in 2,085 idiopathic/heritable (I/H) PAH cases and 9,659 controls of European ancestry using a genome-wide association (GWA) approach. Discovery and replication analyses were conducted in four independent cohorts with genotyping arrays from our US-based PAH Biobank (PAHB) study and three international cohorts with whole genome sequence data. We reported two novel loci, at HLA-DPA1/DPB1 and near SOX17 associated I/H PAH. HLA-DPA/DPB1 locus predicts a reduced annual mortality rate by 25-37% in I/H PAH. The lead SOX17 variant is located in a putative enhancer region in close spatial proximity to the SOX17 gene in endothelial cell (EC) precursors, which influences its expression based on our experimental validation. Our findings provide the first support for the contribution of common genetic variance to PAH risk and, combined with the recently reported data on rare mutations in SOX17 in PAH, highlight the causal role of SOX17 in PAH. Beyond PAH risk, we now hypothesize that PAH progression and outcomes are also genetically modified including from SOX17, a transcription factor, and HLA-DPA1/DPB1 as both novel candidate genes and possible therapeutic targets. To test this hypothesis, we have developed 3 specific aims (SAs) that will further expand the PAHB, the world’s largest PAH biobank, registry, and multi-omics dataset with whole exome sequencing (WES), RNAseq, whole genome genotyping, and non-targeted metabolomics data on nearly all subjects. SA #1 will collect serial longitudinal data in PAHB to interrogate associations between disease risk loci (SOX17, HLA-DPA/B1) with markers of PAH progression. We will also evaluate expression (eQTL) and metabolomics (mQTL) quantitative trait loci analyses for functional validation. Beyond disease risk SOX17/HLA loci, we generated additional preliminary data revealing genome-wide significance for seven novel genetic loci associated directly with survival in PAH in a second, independent PAH cohort. SA #2 will now replicate these new findings with outcomes (progression and survival) collected in PAHB from SA #1. As a unique feature of this proposal, we will interrogate our top loci in two other global PAH cohorts with available eQTL and mQTL data and perform a meta-analysis of all cohorts. We will also construct a risk stratification tool combining clinical risk factors and genetics (SOX17, HLA, 7 SNPs) for PAH outcomes. Finally, based on preliminary data on the protective role of SOX17 in EC function, SA #3 will validate the biological role of SOX17 pathway in the development of PAH using ECs/SMC...