The Genetics of Schizophrenia

Research into the etiology of schizophrenia, particularly the possible genetic basis, has never been as interesting and as provocative as in the past three years. Sullivan looks critically at the key research

Using Animal Models to Disentangle the Role of Genetic, Epigenetic, and Environmental Influences on Behavioral Outcomes Associated with Maternal Anxiety and Depression

The etiology of complex psychiatric disorders results from both genetics and the environment. No definitive environmental factor has been implicated, but studies suggest that deficits in maternal care and bonding may be an important contributing factor in the development of anxiety and depression. Perinatal mood disorders such as postpartum depression occur in approximately 10% of pregnant women and can result in detriments in infant care and bonding. The consequences of impaired maternal–infant attachment during critical early brain development may lead to adverse effects on socioemotional and neurocognitive development in infants resulting in long-term behavioral and emotional problems, including increased vulnerability for mental illness. The exact mechanisms by which environmental stressors such as poor maternal care increase the risk for psychiatric disorders are not known and studies in humans have proven challenging. Two inbred mouse strains may prove useful for studying the interaction between maternal care and mood disorders. BALB/c (BALB) mice are considered an anxious strain in comparison to C57BL/6 (B6) mice in behavioral models of anxiety. These strain differences are most often attributed to genetics but may also be due to environment and gene by environment interactions. For example, BALB mice are described as poor mothers and B6 mice as good mothers and mothering behavior in rodents has been reported to affect both anxiety and stress behaviors in offspring. Changes in gene methylation patterns in response to maternal care have also been reported, providing evidence for epigenetic mechanisms. Characterization of these two mouse inbred strains over the course of pregnancy and in the postpartum period for behavioral and neuroendocrine changes may provide useful information by which to inform human studies, leading to advances in our understanding of the etiology of anxiety and depression and the role of genetics and the environment

What Next in Schizophrenia Genetics for the Psychiatric Genomics Consortium?

Over the last 8 years the Psychiatric Genomics Consortium (PGC; http://pgc.unc.edu) has fundamentally changed the landscape for psychiatric genetics research. This has been achieved through unprecedented teamwork, involving more than 900 investigators from 40 countries, allied to rigorous methodology. Significantly, the PGC has an open-source approach with the main findings freely available for unrestricted use (http://pgc.unc.edu/downloads). Dozens of groups around the world are using PGC data to develop better analytical methods and to perform secondary analyses on a dataset representing more than 400 000 human participants

Schizophrenia genetics: the search for a hard lead

To describe the rationale for searching for genes for schizophrenia, prior efforts via candidate gene association and genomewide linkage studies, and to set the stage for the numerous genomewide association studies that will emerge by the end of 2008

Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Schizophrenia is a heritable disorder with substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases, 6,243 controls) followed by meta-analysis with prior schizophrenia GWAS (8,832 cases, 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls, and 581 trios). In total, 22 regions met genome-wide significance (14 novel and one previously implicated in bipolar disorder). The results strongly implicate calcium signaling in the etiology of schizophrenia, and include genome-wide significant results for CACNA1C and CACNB2 whose protein products interact. We estimate that ∼8,300 independent and predominantly common SNPs contribute to risk for schizophrenia and that these collectively account for most of its heritability. Common genetic variation plays an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this devastating disorder

The public health utility of genome-wide association study results for smoking behavior

New approaches to improve smoking cessation rates are needed. In recent years, substantial progress has been made in understanding the genetics of smoking behavior, and this knowledge may eventually be used to personalize treatment for smokers. Although there are highly significant and reproducible genetic associations, none are yet ready for clinical applications. We suggest that translational research from several disciplines, including behavioral science, ethics and economics, should be performed in parallel with ongoing genome-wide association studies for smoking behavior and pharmacogenetic trials. The coordinated effort of multidisciplinary research teams will help reveal the circumstances under which we can translate genetic insights into clinical practice in the hope of reducing the burden of smoking in society

Methylation age acceleration does not predict mortality in schizophrenia.

Schizophrenia (SCZ) is associated with high mortality. DNA methylation levels vary over the life course, and pre-selected combinations of methylation array probes can be used to estimate "methylation age" (mAge). mAge correlates highly with chronological age but when it differs, termed mAge acceleration, it has been previously associated with all-cause mortality. We tested the association between mAge acceleration and mortality in SCZ and controls. We selected 190 SCZ cases and 190 controls from the Sweden Schizophrenia Study. Cases were identified from the Swedish Hospital Discharge Register with ≥5 specialist treatment contacts and ≥5 antipsychotic prescriptions. Controls had no psychotic disorder or antipsychotics. Subjects were selected if they had died or survived during follow-up (2:1 oversampling). Extracted DNA was assayed on the Illumina MethylationEPIC array. mAge was regressed on age at sampling to obtain mAge acceleration. Using Cox proportional hazards regression, the association between mAge acceleration and mortality was tested. After quality control, the following were available: n = 126 SCZ died, 63 SCZ alive, 127 controls died, 62 controls alive. In the primary analyses, we did not find a significant association between mAge acceleration and SCZ mortality (adjusted p > 0.005). Sensitivity analyses excluding SCZ cases with pre-existing cancer demonstrated a significant association between the Hannum mAge acceleration and mortality (hazard ratio = 1.13, 95% confidence interval = 1.04-1.22, p = 0.005). Per our pre-specified criteria, we did not confirm our primary hypothesis that mAge acceleration would predict subsequent mortality in people with SCZ, but we cannot rule out smaller effects or effects in patient subsets

Dyadic Characteristics and Intimate Partner Violence among Men Who Have Sex with Men

Objective: Although the research community has begun to recognize intimate partner violence (IPV) as an important issue in same-sex relationships, there has been a lack of attention to characteristics of these relationships that may be associated with IPV. In particular, there has been a lack of attention paid to the associations between dyadic characteristics and IPV in same-sex relationships. This paper examined associations between dyadic characteristics, including relationship satisfaction, communal coping and efficacy, and perpetrating and experiencing IPV among a sample of United States men who have sex with men (MSM). Methods: We collected data via an online survey with 528 MSM, who were greater than 18 years of age and reported at least one male sex partner in the last 12 months. The analysis examined dyadic factors associated with reporting of experiencing and perpetrating emotional violence, physical violence, and sexual violence. Results: The prevalence of violence in the sample ranged from nine percent reporting perpetrating sexual violence to 33% of men reporting experiencing emotional violence. MSM who reported greater satisfaction with their relationship or who reported a higher degree of concordance with their partner on lifestyle choices were less likely to report experiencing or perpetrating emotional violence. MSM who perceived a stigma to being in a male same-sex couple were less likely to report experiencing or perpetrating sexual violence. Conclusion: The results presented here demonstrate high levels of IPV among MSM and that dyadic characteristics are associated with the occurrence of IPV. Understanding relationship characteristics associated with increased IPV among same-sex male couples can contribute to the development of more accurate IPV screening tools, and more sensitively and appropriately designed intervention messages. [West J Emerg Med. 2011;12(3):324-332.

Novel Inducers of the Envelope Stress Response BaeSR in Salmonella Typhimurium: BaeR Is Critically Required for Tungstate Waste Disposal

The RpoE and CpxR regulated envelope stress responses are extremely important for SalmonellaTyphimurium to cause infection in a range of hosts. Until now the role for BaeSR in both the Salmonella Typhimurium response to stress and its contribution to infection have not been fully elucidated. Here we demonstrate stationary phase growth, iron and sodium tungstate as novel inducers of the BaeRregulon, with BaeR critically required for Salmonella resistance to sodium tungstate. We show that functional overlap between the resistance nodulation-cell division (RND) multidrug transporters, MdtA, AcrD and AcrB exists for the waste disposal of tungstate from the cell. We also point to a role for enterobactinsiderophores in the protection of enteric organisms from tungstate, akin to the scenario in nitrogen fixing bacteria. Surprisingly, BaeR is the first envelope stress response pathway investigated in S. Typhimurium that is not required for murine typhoid in either ityS or ityR mouse backgrounds. BaeR is therefore either required for survival in larger mammals such as pigs or calves, an avian host such as chickens, or survival out with the host altogether where Salmonella and related enterics must survive in soil and water

Dyadic Characteristics and Intimate Partner Violence among Men Who Have Sex with Men.

OBJECTIVE: Although the research community has begun to recognize intimate partner violence (IPV) as an important issue in same-sex relationships, there has been a lack of attention to characteristics of these relationships that may be associated with IPV. In particular, there has been a lack of attention paid to the associations between dyadic characteristics and IPV in same-sex relationships. This paper examined associations between dyadic characteristics, including relationship satisfaction, communal coping and efficacy, and perpetrating and experiencing IPV among a sample of United States men who have sex with men (MSM). METHODS: We collected data via an online survey with 528 MSM, who were greater than 18 years of age and reported at least one male sex partner in the last 12 months. The analysis examined dyadic factors associated with reporting of experiencing and perpetrating emotional violence, physical violence, and sexual violence. RESULTS: The prevalence of violence in the sample ranged from nine percent reporting perpetrating sexual violence to 33% of men reporting experiencing emotional violence. MSM who reported greater satisfaction with their relationship or who reported a higher degree of concordance with their partner on lifestyle choices were less likely to report experiencing or perpetrating emotional violence. MSM who perceived a stigma to being in a male same-sex couple were less likely to report experiencing or perpetrating sexual violence. CONCLUSION: The results presented here demonstrate high levels of IPV among MSM and that dyadic characteristics are associated with the occurrence of IPV. Understanding relationship characteristics associated with increased IPV among same-sex male couples can contribute to the development of more accurate IPV screening tools, and more sensitively and appropriately designed intervention messages