Epigenetic studies of suicidal behavior

Recent studies have shown an association between gene alterations by epigenetic mechanisms and suicidal behavior. These epigenetic mechanisms are mitotically, and in some cases meiotically, heritable changes in the genome through non-DNA sequence coding processes that alter gene expression as a result of variable changes in environmental stimuli. Genome-wide association studies have been inconsistent in elucidating the association between genes and suicidal behavior, thereby making the heritability of suicidal behavior is unclear. However, recent epigenetic studies have provided evidence that epigenetic mechanisms could deliver the missing link between the heritability of suicidal behavior and the interaction between environment and the genome. The present review provides an in-depth discussion of epigenetic mechanisms that may regulate gene expression in suicidal behavior. The findings of current epigenetic studies on suicidal behavior will also be discussed considering future epigenome-wide association studies on elucidating the contributions of environment and genome on suicidal behavior.     

Monozygotic twins affected with major depressive disorder have greater variance in methylation than their unaffected co-twin

Our understanding of major depressive disorder (MDD) has focused on the influence of genetic variation and environmental risk factors. Growing evidence suggests the additional role of epigenetic mechanisms influencing susceptibility for complex traits. DNA sequence within discordant monozygotic twin (MZT) pairs is virtually identical; thus, they represent a powerful design for studying the contribution of epigenetic factors to disease liability. The aim of this study was to investigate whether specific methylation profiles in white blood cells could contribute to the aetiology of MDD. Participants were drawn from the Queensland Twin Registry and comprised 12 MZT pairs discordant for MDD and 12 MZT pairs concordant for no MDD and low neuroticism. Bisulphite treatment and genome-wide interrogation of differentially methylated CpG sites using the Illumina Human Methylation 450 BeadChip were performed in WBC-derived DNA. No overall difference in mean global methylation between cases and their unaffected co-twins was found; however, the differences in females was significant (P=0.005). The difference in variance across all probes between affected and unaffected twins was highly significant (P<2.2 × 10⁻¹⁶), with 52.4% of probes having higher variance in cases (binomial P-value<2.2 × 10⁻¹⁶). No significant differences in methylation were observed between discordant MZT pairs and their matched concordant MZT (permutation minimum P=0.11) at any individual probe. Larger samples are likely to be needed to identify true associations between methylation differences at specific CpG sites.     

Nutrigenetics,nutrigenomics and inflammatory bowel diseases

Inflammatory bowel disease includes ulcerative colitis and Crohn’s disease, which are both inflammatory disorders of the gastrointestinal tract. Both types of inflammatory bowel disease have a complex etiology, resulting from a genetically determined susceptibility interacting with environmental factors, including the diet and gut microbiota. Genome Wide Association Studies have implicated more than 160 single-nucleotide polymorphisms in disease susceptibility. Consideration of the different pathways suggested to be involved implies that specific dietary interventions are likely to be appropriate, dependent upon the nature of the genes involved. Epigenetics and the gut microbiota are also responsive to dietary interventions. Nutrigenetics may lead to personalized nutrition for disease prevention and treatment, while nutrigenomics may help to understand the nature of the disease and individual response to nutrients.     

A case for antibiotic perturbation of the microbiota leading to allergy development

The use of antibiotics to treat pathogenic bacterial infections has been one of the greatest contributions to human health, yet antibiotic use also perturbs the communities of commensal and symbiotic bacteria that reside in the intestine of mammals. The microbiota are critical for normal immune development and for maintaining intestinal homeostasis, and disruption of the microbiota has been linked to the emergence of allergic disease both in humans and in animal models. The evidence and mechanisms for antibiotic-mediated disruptions leading to the onset of allergic disease at mucosal surfaces is discussed, as well as the future challenges for the field. A more complete understanding of the mechanisms by which the intestinal microbiota modulate allergic disease development will allow for interventions to counter the potentially adverse effects of antibiotic treatment on the microbiota.     

Genetic,genomic and epigenetic studies as tools for elucidating disease pathogenesis in primary Sjögren’s syndrome

Primary Sjögren’s syndrome (pSS) is characterized by lymphoid infiltration of lacrimal and salivary glands leading to xerophthalmia and xerostomia. pSS is a complex disease involving both genetic and environmental risk factors. Technological advances over the past 10 years have revolutionized genetics and genomics research enabling high-throughput characterization and analysis of DNA and RNA in patient samples on a genome-wide scale. Further, application of high-throughput methods for characterization of epigenetic variation, such as DNA methylation status, is increasingly being applied to AID populations and will likely further define additional risk factors for disease risk and outcome. Main results obtain in pSS through these various approaches are reviewed here.     

Genetic Variation Throughout the Folate Metabolic Pathway Influences Negative Symptom Severity in Schizophrenia

Low serum folate levels previously have been associated with negative symptom risk in schizophrenia, as has the hypofunctional 677C>T variant of the MTHFR gene. This study examined whether other missense polymorphisms in folate-regulating enzymes, in concert with MTHFR, influence negative symptoms in schizophrenia, and whether total risk allele load interacts with serum folate status to further stratify negative symptom risk. Medicated outpatients with schizophrenia (n = 219), all of European origin and some included in a previous report, were rated with the Positive and Negative Syndrome Scale. A subset of 82 patients also underwent nonfasting serum folate testing. Patients were genotyped for the MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTR 2756A>G (rs1805087), MTRR 203A>G (rs1801394), FOLH1 484T>C (rs202676), RFC 80A>G (rs1051266), and COMT 675G>A (rs4680) polymorphisms. All genotypes were entered into a linear regression model to determine significant predictors of negative symptoms, and risk scores were calculated based on total risk allele dose. Four variants, MTHFR 677T, MTR 2756A, FOLH1 484C, and COMT 675A, emerged as significant independent predictors of negative symptom severity, accounting for significantly greater variance in negative symptoms than MTHFR 677C>T alone. Total allele dose across the 4 variants predicted negative symptom severity only among patients with low folate levels. These findings indicate that multiple genetic variants within the folate metabolic pathway contribute to negative symptoms of schizophrenia. A relationship between folate level and negative symptom severity among patients with greater genetic vulnerability is biologically plausible and suggests the utility of folate supplementation in these patients.