Latest from the CDC: Functional Genomics of Serotonin Receptor 2A (HTR2A): Interaction of Polymorphism, Methylation, Expression and Disease Association Virginia R. Falkenberg, Brian M. Gurbaxani, Elizabeth R. Unger and Mangalathu S. Rajeevan Full text download Abstract Serotonergic neurotransmission plays a key role in the pathophysiology of neuropsychiatric illnesses. The functional significance of a promoter polymorphism, −1438G/A (rs6311), in one of the major genes of this system (serotonin receptor 2A, HTR2A) remains poorly understood in the context of epigenetic factors, transcription factors and endocrine influences. We used functional and structural equation modeling (SEM) approaches to assess the contributions of the polymorphism (rs6311), DNA methylation and clinical variables to HTR2A expression in chronic fatigue syndrome (CFS) subjects from a population-based study. HTR2A was up-regulated in CFS through allele-specific expression modulated by transcription factors at critical sites in its promoter: an E47 binding site at position −1,438, (created by the A-allele of rs6311 polymorphism), a glucocorticoid receptor (GR) binding site encompassing a CpG at position −1,420, and Sp1 binding at CpG methylation site −1,224. Methylation at −1,420 was strongly correlated with methylation at −1,439, a CpG site that is dependent upon the G-allele of rs6311 at position −1,438. SEM revealed a strong negative interaction between E47 and GR binding (in conjunction with cortisol level) on HTR2A expression. This study suggests that the promoter polymorphism (rs6311) can affect both transcription factor binding and promoter methylation, and this along with an individuals stress response can impact the rate of HTR2A transcription in a genotype and methylation-dependent manner. This study can serve as an example for deciphering the molecular determinants of transcriptional regulation of major genes of medical importance by integrating functional genomics and SEM approaches. Confirmation in an independent study population is required. This study uses patients from the 2006 CDC Pharmacagenomics study, 1994 CDC criteria but with suspicions about how the CDC actually applied these criteria esp re low fatigue thresholds to qualify. Basically, they didn't find much other than a weak association and given doubts over the sample, and the fact that they were looking at expression of the Serotonin Receptor gene in blood (PBMC), rather than the CNS (and gut?) where it is normally transcribed, this probably doesn't amount to much. I was struck by this: we applied structural equation modeling (SEM), a statistical approach that has been widely used in the psychosocial sciences I'm sure that's what the field of Genomics has been missing until now: statistical approaches from the psychosocial sciences.