**Alessia Russo 1,2, Cornelia Di Gaetano 1,2, Giovanni Cugliari 1,2 and Giuseppe Matullo 1,2,\***


Received: 31 January 2018; Accepted: 26 February 2018; Published: 28 February 2018

**Abstract:** Worldwide, hypertension still represents a serious health burden with nine million people dying as a consequence of hypertension-related complications. Essential hypertension is a complex trait supported by multifactorial genetic inheritance together with environmental factors. The heritability of blood pressure (BP) is estimated to be 30–50%. A great effort was made to find genetic variants affecting BP levels through Genome-Wide Association Studies (GWAS). This approach relies on the "common disease–common variant" hypothesis and led to the identification of multiple genetic variants which explain, in aggregate, only 2–3% of the genetic variance of hypertension. Part of the missing genetic information could be caused by variants too rare to be detected by GWAS. The use of exome chips and Next-Generation Sequencing facilitated the discovery of causative variants. Here, we report the advances in the detection of novel rare variants, genes, and/or pathways through the most promising approaches, and the recent statistical tests that have emerged to handle rare variants. We also discuss the need to further support rare novel variants with replication studies within larger consortia and with deeper functional studies to better understand how new genes might improve patient care and the stratification of the response to antihypertensive treatments.

**Keywords:** essential hypertension; blood pressure; genome-wide association studies; exome microarray; next-generation sequencing; rare variants; rare-variants association testing; burden test; sequence kernel association test
