Whole Exome Sequence Analysis of Pulmonary Hypertension in the UK Biobank

Introduction: Pulmonary hypertension (PH) is a progressive disease characterized by adverse remodeling of the lung vasculature and right ventricular failure. While BMPR2 mutations account for the majority of familial pulmonary arterial hypertension (PAH), the predisposing genetic factors in non-familial PH are not well understood. Whole exome sequencing (WES) data from individuals in the UK Biobank (UKB) provides a unique opportunity to interrogate the genetic factors underlying this rare disease. Hypothesis: Rare disruptive coding variants associated with sporadic PH will provide novel mechanistic insights. Methods: Exome sequences were aligned to the GRCh38 reference genome and variants annotated using Variant Effect Predictor. We identified rare (minor allele frequency <1%) high confidence loss-of-function variants using LOFTEE and deleterious missense variants using MetaSVM. We then performed a rare variant burden association study using logistic regression in REGENIE adjusting for age, sex, array, smoking status, and principal components 1-10. These analyses were performed on unrelated individuals identified based on kinship (kinship > 0.0884). We secondarily curated a list of 58 candidate PAH genes based on recent publications of rare variants identified in PAH, as well as the ClinVar database. PH was defined utilizing ICD codes 416.0 (ICD-9), I27.0, I27.2 (ICD-10). Results: 185,586 UKB participants were included; 665 with PH (age 62 years (+/-6), 46% female) and 184,921 controls (age 56 years (+/-8), 55% female). Rare variant association testing did not identify exome-significantly associated genes (p<2.5x10 -7 ), nor nominal associations in candidate PAH genes. Four novel genes with p<0.01 were identified, which included genes important in mitochondrial function ( ACADM ), nicotinic acetylcholine receptor signaling ( MYO18A ), pulmonary surfactant metabolism ( SFTPA1 ) and smooth muscle function ( BEST2 ). Conclusions: We identified putative genes associated with PH in the population which have not been previously implicated in familial PAH. If additional evidence supports the roles of these genes in PH, these findings may provide new therapeutic insights.