‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

Abstract

Although the invention of right heart catheterisation in the 1950s enabled accurate clinical diagnosis of pulmonary arterial hypertension (PAH), it was not until 2000 when the landmark discovery of the causative role of bone morphogenetic protein receptor type II (BMPR2) mutations shed new light on the pathogenesis of PAH. Since then several genes have been discovered, which now account for around 25% of cases with the clinical diagnosis of idiopathic PAH. Despite the ongoing efforts, in the majority of patients the cause of the disease remains elusive, a phenomenon often referred to as “missing heritability”. In this review, we discuss research approaches to uncover the genetic architecture of PAH starting with forward phenotyping, which in a research setting should focus on stable intermediate phenotypes, forward and reverse genetics, and finally reverse phenotyping. We then discuss potential sources of “missing heritability” and how functional genomics and multi-omics methods are employed to tackle this problem.

Common Variation in EDN1 Regulatory Regions Highlights the Role of PPARγ as a Key Regulator of Endothelin in vitro

“…Pulmonary Arterial Hypertension is a complex disease where genetic information is limited to the main causal genes and little is known about the role of common variation (30,31). Over the last decades, the capability of detecting genetic variation has increased; we can now try to use common variation to explain phenotypic expressivity.…”

Common variation in EDN1 regulatory regions highlights the role of PPARγ as a key regulator of Endothelin in vitro

“…PAH is a complex disease where genetic information is limited to the main causal genes and little is known about the role of common variation 29,30 . Over the last decades, the capability of detecting genetic variation has increased; we can now try to use common variation to explain phenotypic expressivity.…”

Pulmonary Arterial Hypertension: A Deeper Evaluation of Genetic Risk in the -Omics Era

“…An intriguing approach is the assessment of stable intermediate phenotypes that, in turn, leads to a fluid interplay between forward and reverse genetics and reverse phenotyping. Whilst conceptual in nature, this study nonetheless suggests multi-omics approaches to otherwise intractable genetic disorders may yield subtle and/or masked insights into PAH pathogenesis [7].…”