The implications of the shared genetics of psychiatric disorders

Recent genomic studies have revealed the highly polygenic nature of psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. Many of the individual genetic associations are shared across multiple disorders in a way that points to extensive biological pleiotropy and further challenges the biological validity of existing diagnostic approaches. Here we argue that the existence of risk alleles specific to a single diagnostic category is unlikely. We also highlight some of the important clinical repercussions of pleiotrop

Genetics of schizophrenia

Schizophrenia is a common psychiatric disorder with a strong genetic component. Recent studies applying new genomic technology to large samples have yielded substantial advances in identifying specific, associated DNA variants as well as clarifying the underlying genetic architecture of the disorder. The genetic liability of schizophrenia is now established as polygenic, with risk alleles in many genes existing across the full allelic frequency spectrum. It has also become apparent that schizophrenia shares risk alleles with other neuropsychiatric phenotypes, such as bipolar disorder, major depressive disorder, autism spectrum disorder, intellectual disability and attention-deficit hyperactivity disorder. These risk variants aggregate in several sets of functionally related genes, thereby providing novel insights into disease pathogenesis and opportunities for research into discovering new treatments

Schizophrenia genetics: Building the foundations of the future

In recent years, our understanding of the genetic architecture of schizophrenia, a phrase which denotes the numbers of risk variants, their frequencies and effect sizes, has been transformed. This has come about through advances in technology that have allowed almost the entire human genome to be simultaneously interrogated for the presence of disease-associated genetic variation and allows this to be performed in sample sizes powered for a realistic possibility of success. Another development has been the emergence of international consortia willing to share raw data and their coalescence into super-consortia to achieve sample sizes and bodies of clinical and analytic expertise that was unimaginable a decade ago. These innovations have driven the emergence of statistically robust and replicable genetic findings in schizophrenia, and a rapid escalation in the number of those findings over the last 5 years. The latest example comes from the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC-SCZ) which, at the time of publication, included contributions from around 37 000 individuals with schizophrenia, 302 investigators, 35 countries, and 4 continents.1 In their recent paper, published in Nature in July 2014, the PGC-SCZ group report 128 statistically independent genetic associations, implicating a minimum of 108 conservatively defined schizophrenia-associated genetic loci.1 Of the identified loci, 83 have not been previously robustly supported as playing a role in schizophrenia, but it is also important to note the findings are consistent with previous literature; 25 loci that had previously been reported as associated with schizophrenia in large samples were again supported in this much larger analysis, confirming that the use of large samples and stringent statistical cut-offs results in reproducible findings. The availability of so many robustly supported findings offers immense opportunities for investigating and advancing our understanding of etiology

Gender differences in CNV burden do not confound schizophrenia CNV associations

Compared with the general population, an excess of rare copy number variants (CNVs) has been identified in people with schizophrenia. Females with neurodevelopmental disorders and in the general population have been reported to carry more large, rare CNVs than males. Given that many schizophrenia datasets do not have equal gender ratios in cases and controls, sex differences in CNV burden might have impacted on estimates of case-related CNV burden and also on associations to individual loci. In a sample of 13,276 cases and 17,863 controls, we observed a small but significant excess of large (≥500 Kb), rare (<1%) CNVs in females compared with males in both cases and controls (OR = 1.17, P = 0.0012 for controls; OR = 1.11, P = 0.045 for cases). The burden of 11 schizophrenia-associated CNVs was significantly higher in female cases compared with male cases (OR = 1.38, P = 0.0055), but after accounting for the rates of CNVs in controls, we found no significant gender difference in the risk conferred by these loci. Controlling for gender had a negligible effect on the significance of association between specific CNVs and schizophrenia. The female excess of large CNVs in both cases and controls suggests a female protective mechanism exists for deleterious CNVs that may extend beyond neurodevelopmental phenotypes

Peptidomic analysis of the host-defense peptides in skin secretions of the Amazon River frog Lithobates palmipes (Ranidae)

International audienc

Reasons for discontinuing clozapine: a cohort study of patients commencing treatment

Background Clozapine is uniquely effective in the management of treatment-resistant schizophrenia (TRS). However, a substantial proportion of patients discontinue treatment and this carries a poor prognosis. Methods We investigated the risk factors, reasons and timing of clozapine discontinuation in a two-year retrospective cohort study of 316 patients with TRS receiving their first course of clozapine. Reasons for discontinuation of clozapine and duration of treatment were obtained from case notes and Cox regression was employed to test the association of baseline clinical factors with clozapine discontinuation. Results A total of 142 (45%) patients discontinued clozapine within two years. By studying the reasons for discontinuations due to a patient decision, we found that adverse drug reactions (ADRs) accounted for over half of clozapine discontinuations. Sedation was the most common ADR cited as a reason for discontinuation and the risk of discontinuation due to ADRs was highest in the first few months of clozapine treatment. High levels of deprivation in the neighbourhood where the patient lived were associated with increased risk of clozapine discontinuation (HR = 2.12, 95% CI 1.30–3.47). Conclusions Living in a deprived neighbourhood was strongly associated with clozapine discontinuation. Clinical management to reduce the burden of ADRs in the first few months of treatment may have a significant impact and help more patients experience the benefits of clozapine treatment

Investigation of the genetic association between quantitative measures of psychosis and schizophrenia:A polygenic risk score analysis

The presence of subclinical levels of psychosis in the general population may imply that schizophrenia is the extreme expression of more or less continuously distributed traits in the population. In a previous study, we identified five quantitative measures of schizophrenia (positive, negative, disorganisation, mania, and depression scores). The aim of this study is to examine the association between a direct measure of genetic risk of schizophrenia and the five quantitative measures of psychosis. Estimates of the log of the odds ratios of case/control allelic association tests were obtained from the Psychiatric GWAS Consortium (PGC) (minus our sample) which included genome-wide genotype data of 8,690 schizophrenia cases and 11,831 controls. These data were used to calculate genetic risk scores in 314 schizophrenia cases and 148 controls from the Netherlands for whom genotype data and quantitative symptom scores were available. The genetic risk score of schizophrenia was significantly associated with case-control status (p<0.0001). In the case-control sample, the five psychosis dimensions were found to be significantly associated with genetic risk scores; the correlations ranged between.15 and.27 (all p<.001). However, these correlations were not significant in schizophrenia cases or controls separately. While this study confirms the presence of a genetic risk for schizophrenia as categorical diagnostic trait, we did not find evidence for the genetic risk underlying quantitative schizophrenia symptom dimensions. This does not necessarily imply that a genetic basis is nonexistent, but does suggest that it is distinct from the polygenic risk score for schizophrenia

PP2A inhibition overcomes acquired resistance to HER2 targeted therapy

Background: HER2 targeted therapies including trastuzumab and more recently lapatinib have significantly improved the prognosis for HER2 positive breast cancer patients. However, resistance to these agents is a significant clinical problem. Although several mechanisms have been proposed for resistance to trastuzumab, the mechanisms of lapatinib resistance remain largely unknown. In this study we generated new models of acquired resistance to HER2 targeted therapy and investigated mechanisms of resistance using phospho-proteomic profiling. Results: Long-term continuous exposure of SKBR3 cells to low dose lapatinib established a cell line, SKBR3-L, which is resistant to both lapatinib and trastuzumab. Phospho-proteomic profiling and immunoblotting revealed significant alterations in phospho-proteins involved in key signaling pathways and molecular events. In particular, phosphorylation of eukaryotic elongation factor 2 (eEF2), which inactivates eEF2, was significantly decreased in SKBR3-L cells compared to the parental SKBR3 cells. SKBR3-L cells exhibited significantly increased activity of protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates eEF2. SKBR3-L cells showed increased sensitivity to PP2A inhibition, with okadaic acid, compared to SKBR3 cells. PP2A inhibition significantly enhanced response to lapatinib in both the SKBR3 and SKBR3-L cells. Furthermore, treatment of SKBR3 parental cells with the PP2A activator, FTY720, decreased sensitivity to lapatinib. The alteration in eEF2 phosphorylation, PP2A activity and sensitivity to okadaic acid were also observed in a second HER2 positive cell line model of acquired lapatinib resistance, HCC1954-L. Conclusions: Our data suggests that decreased eEF2 phosphorylation, mediated by increased PP2A activity, contributes to resistance to HER2 inhibition and may provide novel targets for therapeutic intervention in HER2 positive breast cancer which is resistant to HER2 targeted therapies