Prediction of susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factors

Major depressive disorder (MDD) is the most common psychiatric disorder and the second overall cause of disability. Even though a significant amount of the variance in the MDD phenotype is explained by inheritance, specific genetic variants conferring susceptibility to MDD explain only a minimal proportion of MDD causality. Moreover, genome-wide association studies have only identified two small-sized effect loci that reach genome-wide significance. In this study, a group of Mexican-American patients with MDD and controls recruited for a pharmacogenetic study were genotyped for nonsynonymous single-nucleotide polymorphisms (nsSNPs) and used to explore the interactions of multiple functional genetic variants with risk-classification tree analysis. The risk-classification tree analysis model and linkage disequilibrium blocks were used to replicate exploratory findings in the database of genotypes and phenotypes (dbGaP) for major depression, and pathway analysis was performed to explore potential biological mechanisms using the branching events. In exploratory analyses, we found that risk-classification tree analysis, using 15 nsSNPs that had a nominal association with MDD diagnosis, identified multiple increased-MDD genotype clusters and significant additive interactions in combinations of genotype variants that were significantly associated with MDD. The results in the dbGaP for major depression disclosed a multidimensional dependent phenotype constituted of MDD plus significant modifiers (smoking, marriage status, age, alcohol abuse/dependence and gender), which then was used for the association tree analysis. The reconstructed tree analysis for the dbGaP data showed robust reliability and replicated most of the genes involved in the branching process found in our exploratory analyses. Pathway analysis using all six major events of branching (PSMD9, HSD3B1, BDNF, GHRHR, PDE6C and PDLIM5) was significant for positive regulation of cellular and biological processes that are relevant to growth and organ development. Our findings not only provide important insights into the biological pathways underlying innate susceptibility to MDD but also offer a predictive framework based on interactions of multiple functional genetic variants and environmental factors. These findings identify novel targets for therapeutics and for translation into preventive, clinical and personalized health care

Effects of denervation on 3 H-fucose incorporation by odontoblasts in the mouse incisor

The present study was designed to determine the effects of denervation on glycoprotein synthesis in the predentinal matrix of the mouse incisor. The inferior alveolar nerve (IAN), superior cervical ganglion (SCG) or both (IAN+SCG) were unilaterally resected in adult mice with the contralateral side remaining intact as a control. Fourteen days after surgery and 4 h prior to killing, 0.2 mCi of 3 H-fucose was injected intravenously and mandibles were processed for standard histological and autoradiographic techniques. Silver halide grains were counted over the predentin matrix for 2000 μm per tooth. The results showed that the IAN and SCG resection affected 3 H-fucose incorporation into the predentinal matrix; however, the highest absolute mean grain counts occurred after IAN+SCG resection. SCG resection increased the amount of 3 H-fucose incorporated into the predentinal matrix by 48%, that of IAN by 24% and that of IAN+SCG by 14% as compared to contralateral controls. These data indicate a regulatory role for the nervous system and a possible interaction of neural components in the control of glycoprotein synthesis by odontoblasts in the mouse incisor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47677/1/441_2004_Article_BF00216039.pd