There is accumulating evidence of a genetic predisposition for developing a functional gastrointestinal (GI) disorder. Identification of the genetic factors may improve understanding of underlying pathophysiological mechanisms. We aimed to test the association of functional polymorphisms in genes involved in serotonergic signalling and G-protein-mediated signal transduction, both affecting gastroduodenal sensory and motor function, with functional dyspepsia (FD). FD patients, send to our tertiary referral centre, were studied (n = 112). Healthy controls (n = 336) free of GI symptoms were matched 1 : 3 for age and gender. Polymorphisms in genes encoding the serotonin receptor type three A subunit (HTR3A), the serotonin transporter (SERT) and the G-protein beta3 subunit (GNB3) were analysed. The FD patients displayed a higher prevalence of the T allele of the GNB3 C825T polymorphism compared to healthy controls (OR = 1.60, 95% CI: 1.03-2.49, P = 0.038). No association between FD and the genotype of the insertion/deletion polymorphism in the promoter of SERT (SERT-P) or HTR3A C178T polymorphism was observed. Tertiary referral FD is associated with the 825T allele of the GNB3 gene. The increased signal transduction associated with this allele may contribute to the abnormalities in gastroduodenal sensory and motor function observed in FD.