Schizophrenia / Bipolar Disorder Susceptibility Gene GNBIL MRNA Expression Regulation

GNB1L [guanine nucleotide binding protein (G protein), beta polypeptide 1-like] and TBX1 (T-box 1) are adjacent, convergently transcribed ("tail-to-tail") genes located within chromosome region 22q11.2. Hemizygous deletions of 1.5-3M bp in this region cause 22q11.2 deletion syndrome (22qll.2DS), characterized by multiple developmental abnormalities affecting the face and heart and a high incidence of psychiatric disorders, including schizophrenia. Case-control studies in European and Han Chinese population have reported that single nucleotide polymorphism (SNPs) located within GNB1L are associated with schizophrenia and bipolar disorder.To understand the expression regulatory pattern of GNB1L and TBXl, and determine whether high or low levels of mRNA expression are associated with disorders, we measured relative and allele-specific expression of GNB1L and TBX1 mRNA in 52 independent samples of Han Chinese prefrontal cortex. In addition, whole genome genotyping was carried out suing DNA isolated from each sample. Our results suggest GNB1L is regulated by one or more cis-acting genetic variants located within the 3’-end of the gene. Significantly, linkage disequilibrium (LD) analysis indicated that the putative regulatory variant(s) are located within a haploblock containing the SNPs previously shown to associate with schizophrenia and bipolar disorder. By contrast, our data did not identify any genetic variants statistically associated with TBX1 expression. Based on this study, we conclude that GNB1L mRNA expression is associated with schizophrenia and bipolar disorder and the low-expression allele is the risk allele.In addition to our studies of GNB1L and TBX, mRNA expression, we also established a novel mathematical framework for modeling log2AEI population distributions. Using this framework, we are able to make quantitative predictions concerning the number, location and contributions of cis-acting genetic regulatory elements for genes of interest. We believe that mathematical modeling of allele-specific mRNA repression will facilitate the identification of regulatory genetic variants for candidate disorder gene and the development of more effective markers for genetic case-control association studies.