OBJECTIVE: Functional somatic syndromes commonly occur together, share a genetic component and are associated with numerous somatic symptoms. This study aimed to determine if genetic variation in two neuroendocrine systems, the serotoninergic system and the hypothalamic-pituitary-adrenal (HPA) axis, was associated with the number of reported somatic symptoms. METHODS: This population-based cohort study (Epidemiology of Functional Disorders) recruited participants from three primary care registers in the northwest of England. Somatic symptoms, anxiety, depression, and pain were assessed using the Somatic Symptoms Checklist, Hospital Anxiety and Depression scales, and body manikins, respectively, via a postal questionnaire. Tag Single Nucleotide Polymorphisms (SNPs) (r(2)>0.8) were selected for serotoninergic system genes (TPH2, SLC6A4 and HTR2A) and HPA axis genes (CRH, CRHR1, CRHBP, MC2R, POMC, NR3C1, and SERPINA6) and genotyped using Sequenom technology. Negative binomial regression was used to test for association between SNPs and the number of somatic symptoms. Stepwise-regression was used to identify independent effects and adjustments were made for anxiety, depression, and pain. RESULTS: A total of 967 subjects were successfully genotyped for 143 (87%) SNPs. Multiple SNP associations with the number of somatic symptoms were observed in HTR2A and SERPINA6 as well as two SNPs in TPH2. Stepwise regression identified two effects in HTR2A and a single effect in TPH2 which were independent of anxiety, depression, and pain. A single effect was also identified in SERPINA6 but was no longer significant when adjusted for pain. CONCLUSION: This study finds association of SNPs in HTR2A, SERPINA6, and TPH2 with somatic symptoms implicating them as potentially important in the shared genetic component to functional somatic syndromes, although replication is required.