Herein we review the role of variants of GNAS [guanine nucleotide binding protein (G protein), alpha] that encode the ubiquitous Gαs-subunit; variants of GNB1 (GNB, G protein subunit beta) that encode the Gβ subunits and that are associated with phenotypes such as essential hypertension and obesity; and variants of RGS4 (RGS, regulator of G protein signaling) that encode a regulator of G protein signaling associated with essential hypertension. Here, PITX2 is linked to essential hypertension.