(DOWNLOAD) "Exploration of Functional Genetic Variants in Candidate Genes for Psychiatric Disorders" by Robert Moyer * Book PDF Kindle ePub Free
eBook details
- Title: Exploration of Functional Genetic Variants in Candidate Genes for Psychiatric Disorders
- Author : Robert Moyer
- Release Date : January 21, 2013
- Genre: Medical,Books,Professional & Technical,
- Pages : * pages
- Size : 10334 KB
Description
Drug addiction is a chronic disorder characterized by compulsive drug seeking and drug taking despite serious negative consequences. While twin studies indicate a significant contribution of genetic factors to an individual’s susceptibility to addiction, identifying and replicating significant genetic associations for addiction has proven difficult. Association studies have identified a number of candidate genes harboring variants associated with susceptibility to addiction, but the causative variants frequently remain unknown. Instead, the association is found between the disease and a polymorphism that is linked to the causal variant. As allele frequencies and linkage patterns may vary between populations, associations found are frequently not replicated in follow-up studies, in part due to a lack of consideration of the molecular mechanisms underlying the effects of the polymorphisms. A solution to this problem is the thorough characterization of functional genetic polymorphisms and their effects on regulation of candidate genes for addiction and other psychiatric disorders. Historically, many genetic studies have focused on nonsynonymous single nucleotide polymorphisms (SNPs) that alter amino acid sequence, even though regulatory polymorphisms in non-protein coding regions are likely to be more prevalent. Regulatory polymorphisms can result in altered transcription, alternative splicing, and mRNA folding and stability, to name but a few mechanisms. The first step in our approach is to measure allelic mRNA expression and/or differential expression of functionally distinct splice variants for candidate genes in relevant brain regions from human autopsies. We use these measurements as phenotypic traits to identify causative genetic variants affecting the amount and/or nature of the mRNA. Finally, we test the putative functional variant for association with human phenotype to establish its clinical relevance. I focused on a number of candidate genes for drug addiction, and made some novel and significant findings: 1) The effects of two intronic SNPs in the human dopamine receptor D2 (DRD2) gene, previously shown to alter DRD2 alternative splicing, were confirmed in human brain autopsy tissues (putamen and prefrontal cortex) obtained from a population of cocaine abusers and controls. The same SNPs were significantly associated with cocaine abuse with an odds ratio of ~2. Furthermore, I detected a significant interaction between these SNPs and a functional variant in the dopamine transporter (DAT) gene in the same population. 2) A synonymous SNP in the human beta-arrestin2 (ARRB2) gene was associated with a small but significant increase in ARRB2 mRNA expression in prefrontal cortex obtained from Alzheimer’s patients. However, there was no genotype effect on beta-arrestin2 protein levels in the same samples. 3) I identified a number of samples with significant allelic expression imbalance (AEI) of DRD3 mRNA in nucleus accumbens obtained from a cohort of normal controls and patients diagnosed with schizophrenia, bipolar disorder, or depression, indicating the presence of a cis-acting regulatory variant affecting mRNA expression. However, none of the 11 SNPs genotyped across the DRD3 gene locus could account for the observed AEI. Identification of functional genetic variants and characterization of the underlying molecular genetic mechanisms are critical for interpretation of clinical association studies and selection of valid biomarkers affecting disease susceptibility and treatment response. The striking association of the DRD2 SNPs with cocaine abuse supports the notion that the modulation of DRD2 alternative splicing is an important regulator of dopaminergic activity with phenotypic consequences, although the data do not prove a causative link between alternative splicing and cocaine abuse. The results of this study contribute to our understanding of the functional genetic variation in three important candidate genes and have the potential to improve the treatment of drug addiction and other psychiatric disorders.