Functional variants of TSPAN8 are associated with bipolar disorder and schizophrenia

Tetraspanins affect protein trafficking and are known to influence a wide variety of physiologic processes. Recently, single nucleotide polymorphisms (SNPs) of the tetraspanin gene TSPAN8 were found among the best ranked markers of genome wide association studies on bipolar disorder (BPD) (rs1705236) and type-2 diabetes, but functional consequences remained largely unknown. In the present study, we examined 13 tagging SNPs covering the TSPAN8 gene, the intronic TSPAN8 SNP rs1705236 as well as two non-synonymous (ns) SNPs in schizophrenia (SCZ) and BPD samples. In our analysis setting, we were not able to replicate the association of rs1705236 with BPD, nor did we find an association with SCZ. In the TSPAN8 upstream transcriptional control region however, we found rs4500567 to be associated with BPD. In contrast, in SCZ the nsSNP rs3763978 was associated with disease. The significance of both associations withstood conservative Bonferroni correction. In an attempt to link the polymorphisms to functional consequences, we performed an allele-specific in silico mapping of transcription factor binding sites around rs4500567 and predicted the tolerance of the Gly73Ala exchange caused by rs3763978. The results argue for a differential promoter activity specific for the variant associated with BPD, but impaired protein functionality in SCZ. This suggests that TSPAN8 contributes to both diseases, yet with different underlying mechanisms: regulatory versus structural. Similar phenomena might also occur in other risk genes for both BPD and SCZ, providing a molecular basis for the genetic overlap of both entities.