TGFB1 rs8179181 polymorphism is reproducibly associated with Parkinson's disease in a Spanish population

There is evidence that transforming growth factor (TGF)-{beta} signaling participates in the pathology of Parkinsons disease (PD). Dampened TGF-{beta} signaling in Smad3- or T{beta}RII-deficient mice leads to the appearance of -synuclein inclusions in the brain, as well as dopaminergic, motor, and cognitive deficits. Accordingly, we hypothesized that genetic variants of TGFB/SMAD could be risk factors for PD in humans. Here, we present two independent case-control studies aimed at evaluating the association between genetic variants of six genes related to TGF-{beta} signaling (TGFB1, TGFB2, TGFBRI, TGFBRII, SMAD3 and SMAD2) and the development of sporadic PD. A total of 275 unrelated Spanish Caucasian individuals were included in the study (141 cases and 134 controls), with 132 individuals in the discovery phase and 143 individuals in the replication phase. Next-generation sequencing identified a total of 409 variants in the coding, splicing, and untranslated regions of these genes. Analysis of common variants in the discovery phase revealed an association between PD and the TGFB1 rs8179181 variant, which was further confirmed in the replication phase [odds ratio (OR) 0.48, 95% confidence interval (CI) 0.32-0.73, p = 0.00057). A weak association of the SMAD3 rs11556089 polymorphism with PD was also detected (OR 0.49, 95% CI 0.26-0.93, p = 0.0375). Seven haplotypes were identified; however, there were no significant differences in their frequencies between patients with PD and controls. In conclusion, both the discovery and replication phases of this study suggest that the rs8179181 variant of TGFB1 represents a novel susceptibility locus for PD. HIGHLIGHTSO_LIDeficient TGF-{beta} signalling via Smad3 induces the formation of -synuclein aggregates and a parkinsonian pathology in mice. C_LIO_LITGFB1, TGFB2, TGFBRI, TGFBRII, SMAD3 and SMAD2 genes were sequenced to search for associations of their allelic variants with idiopathic PD. C_LIO_LITwo independent case-control studies of Spanish Caucasian individuals identified 409 genetic variants in their coding, splicing and UTR regions. C_LIO_LIThe rs8179181 SNP in TGFB1 was reproducibly associated with idiopathic PD, representing a novel PD susceptibility locus. C_LI