Abstract Body (Do not enter title and authors here): Background: Rare Mendelian drivers of pulmonary arterial hypertension (PAH) have been identified, but the contributions of common genetic variation to pulmonary pressure in other causes of pulmonary hypertension (PH) are not well understood.

Research Questions: To identify common genetic variants associated with estimated pulmonary pressure in two large patient populations undergoing clinically indicated echocardiography (echo).

Methods: Echo estimates of pulmonary artery systolic pressure (ePASP) were extracted from the Million Veterans Program (MVP) and Vanderbilt’s BioVU using a published algorithm. Genome wide association study (GWAS) and trans-ancestral meta-analysis of highest measured ePASP were performed using genomic data from MVP participants with replication of lead SNPs in BioVU.

Results: Among 158,739 MVP participants (94% male; 72% European, 20% African, 7% Hispanic, 1% Asian ancestry), the median age was 67 (IQR 61-73), median BMI was 29.2 (IQR 25.8-33.4), and median ePASP was 34.9 (IQR 27.5 – 43.2) mmHg. Trans-ancestry GWAS meta-analysis in 148,464 MVP participants identified genomic loci associated with ePASP at genome-wide significance (5x10^-8) near KCNK3, SCN10, CDKN1A, TMEM8C, BDNF, and FTO genes (Figure 1). Phenome wide association studies of lead SNPs identified PAH, cardiac diseases, and metabolic disorders as sharing genetic risk for ePASP. The lead SNP near KCNK3, rs1275985 (MAF 47%), remained significant when GWAS was conducted using tricuspid regurgitation velocity (0.018+0.006 mmHg/allele) and in a case-control analysis using ePASP > 40 as the threshold for PH (0.056+0.018 log OR/allele). Replication of the lead SNPs in the BioVU cohort confirmed rs1275985 as the only SNP significantly associated with ePASP (p < 0.05/7), which persisted in case-control analysis of PH in BioVU at various thresholds (Figure 2) and when stratified comorbid heart failure (Figure 3).

Conclusions: We conducted the largest GWAS of ePASP to date with replication of significant SNPs near KCNK3 in a second cohort. KCNK3 mutations have been implicated in Mendelian causes of PAH. This study suggests that genetic variation near KCNK3 may broadly affect PH risk across different subtypes of PH as well.