ABSTRACT
OBJECTIVE: The OPRM1 gene was studied for DNA methylation in opioid dependence and possible paternal contribution to epigenetic inheritance of altered methylation profiles. PARTICIPANTS AND METHODS: DNA was extracted from blood and sperm from 13 male opioid addicts and 21 male control subjects. DNA methylation was determined by pyrosequencing in 24 CpG sites at the OPRM1 promoter region. RESULTS: The authors found significantly increased overall methylation in blood DNA from addicted subjects (Kruskal-Wallis [K-W] p = 0.013). Seven CpG sites showed significantly hypermethylated blood DNA from cases when compared with blood DNA from controls (p < 0.05 at CpGs 5, 9, 10, 11, 18, 23, and 24). In sperm-derived DNA from addicts, the methylation was significantly increased at CpG 2 (p = 0.012), and overall methylation did not reach significant difference (K-W p = 0.523). CONCLUSIONS: Increased DNA methylation in the OPRM1 gene is associated with opioid dependence. Hypermethylated CpG sites located in OPRM1 promoter may potentially block the binding of Sp1 and other transcription activators, thus leading to OPRM1 silencing. The increased DNA methylation in sperm may suggest a way of epigenetic heritability of opioid abuse or dependence phenotypes.
Subject(s)
CpG Islands , DNA Methylation , Opioid-Related Disorders/genetics , Promoter Regions, Genetic , Receptors, Opioid, mu/genetics , Spermatozoa/metabolism , Adult , Analysis of Variance , Case-Control Studies , Discriminant Analysis , Genetic Predisposition to Disease , Heredity , Heroin Dependence/blood , Heroin Dependence/genetics , Humans , Male , Missouri , Opioid-Related Disorders/blood , Pedigree , Sequence Analysis, DNA , Up-RegulationABSTRACT
Several studies have implicated an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (SLC6A4; 5-HTT) in the development of mood disorders. In the present study of a sample of 247 young adult female twins from Missouri, we examine whether this polymorphism interacts with the effect of adverse life events to increase risk for developing depression. We found a significant interaction between the number of high-activity L(A) alleles and exposure to trauma (OR = 1.70, P < 0.0001). This differs from previous reports, in that the higher activity genotypes (L(A)/L(A), L(A)/S, L(A)/L(G)), rather than the low activity genotypes (S/S, S/L(G), L(G)/L(G)), are associated with an increased incidence of major depressive disease (MDD) in the presence of environmental trauma.
Subject(s)
Depressive Disorder, Major/etiology , Depressive Disorder, Major/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Wounds and Injuries/complications , Adolescent , Adult , Alleles , Female , Genotype , Humans , Prospective Studies , Risk FactorsABSTRACT
Several studies provide suggestive evidence of a susceptibility locus for bipolar disorder at chromosome 21q22-23. In an attempt to replicate these findings, we have analyzed linkage to 11 polymorphic markers from this region in 18 Bulgarian pedigrees with affective disorder. Two-point linkage analysis under assumption of homogeneity and a dominant model with reduced penetrance produced modest positive values for some of the markers tested under a 'narrow' phenotype definition, including bipolar I and II, and schizoaffective disorder. The maximum two-point score (lod=1.76, theta=0.00) was at marker D21S1919. Non-parametric linkage analysis under the same phenotype model, yielded positive NPLall values (P<0.05) over the region between markers D21S211 and D21S416, with a peak at D21S1252 (NPL Zall=2.32, P=0.0003). The multipoint lod score (GENEHUNTER) reached a suggestive value for linkage (lod=2.10) also at marker D21S1252. The results under a recessive model were completely negative. These data add to the evidence for the existence of a susceptibility locus for bipolar affective disorder on chromosome 21q22.
