The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) plays a crucial role in developing and adult brain. Disruption of serotonergic activity has been proposed to contribute to major mental and neurodevelopmental disorders, including autism, major depression, anxiety disorders and schizophrenia. How serotoninergic activity is affected by genetic differences among individuals, however, is poorly understood. We hypothesize that genetic variants causing exceptionally high- or low-levels of gene expression alter the development of the brain in ways that predispose certain individuals to develop serious disorders as children or adults. The goal of this study is to identify common genetic variants (polymorphisms) that regulate the expression of key serotonin-related genes in developing and adult human brain. Using autopsy tissue samples, we will quantify the expression of mRNAs for 15 serotonin-related genes in developing and adult pons, hippocampus and frontal cortex in an allele-specific manner. Quantifying levels of mRNA produced from two alleles within each brain sample allows allele-specific differences in expression to be detected without making comparisons between samples. This novel approach greatly increases the accuracy and reproducibility of the measurements. Based upon our previous experience, we expect 3-4 of our selected genes to show significant and frequent allelic expression imbalance (AEI) in developing and/or adult brain. AEI is caused by regulatory polymorphisms located within or near the corresponding gene. Since expression is context-dependent, it is possible that the extent of AEI differs between brain regions and/or between developing and adult brain. One of the major objectives of this project is to determine whether AEI for certain genes occurs only in the developing brain, as has been proposed for the serotonin transporter (SERT). For genes that show AEI, we will search the neighborhood of the gene for single nucleotide polymorphisms (SNPs) for which heterozygosity correlates with AEI. Highly correlated SNPs will be further studied to determine whether they play a direct role in mRNA expression. We will first focus on AEI mechanisms for tryptophan hydroxylase 2 (TPH2) for which we have previously identified several highly correlated SNPs. Validated regulatory polymorphisms in TPH2 and other serotonin-related genes will be valuable biomarkers for diagnosing and analyzing major mental and neurodevelopmental disorders. -Relevance The goal of this study is to identify common regulatory variants in genes related to serotonin, a neurotransmitter that plays important roles in the developing and adult brain. We hypothesize that genetic variants that significantly alter the expression of key serotonin-related genes contribute to mental and neurodevelopmental disorders, including autism, major depression, anxiety disorders and schizophrenia. Identifying genetic variants that regulate key serotonin-related genes will be a significant step toward developing new methods for the diagnosis, treatment and, possibly, prevention of these disorders. ? ?
| Johnson, Andrew D; Zhang, Ying; Papp, Audrey C et al. (2008) Polymorphisms affecting gene transcription and mRNA processing in pharmacogenetic candidate genes: detection through allelic expression imbalance in human target tissues. Pharmacogenet Genomics 18:781-91 |
