Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

/pdf/finding-the-missing-heritability-of-complex-diseases-3b6mbqztnq.pdf

Finding the missing heritability of complex diseases

Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

/pdf/common-polygenic-variation-contributes-to-risk-of-3uqwavl1v9.pdf

Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.

10 Years of GWAS Discovery: Biology, Function, and Translation

G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neurotransmission have been clinically used in the management of several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, Huntington's disease, attention deficit hyperactivity disorder (ADHD(1)), and Tourette's syndrome. Numerous advances have occurred in understanding the general structural, biochemical, and functional properties of dopamine receptors that have led to the development of multiple pharmacologically active compounds that directly target dopamine receptors, such as antiparkinson drugs and antipsychotics. Recent progress in understanding the complex biology of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their primary action on cAMP-mediated signaling, dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as β-arrestins. One of the future directions in managing dopamine-related pathologic conditions may involve a transition from the approaches that directly affect receptor function to a precise targeting of postreceptor intracellular signaling modalities either directly or through ligand-biased signaling pharmacology. In this comprehensive review, we discuss dopamine receptor classification, their basic structural and genetic organization, their distribution and functions in the brain and the periphery, and their regulation and signal transduction mechanisms. In addition, we discuss the abnormalities of dopamine receptor expression, function, and signaling that are documented in human disorders and the current pharmacology and emerging trends in the development of novel therapeutic agents that act at dopamine receptors and/or on related signaling events.

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

https://www.cell.com/cell-chemical-biology/pdf/S1074-5521(15)00199-4.pdf

Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency

We link schizophrenia in families from the genetically isolated South African Afrikaner population to chromosome 13q (n =51), 1p (n =23) and combined 13q & 1p (n =18). Patients with linkages to chromosome 13q were 4.16 times more likely to meet diagnostic criteria for schizoaffective disorder compared to patients with linkage to 1p. A third of patients with linkage to both 13q &1p met diagnostic criteria for SAD. There was a significant positive relationship between suicidality and a diagnosis of schizoaffective disorder. Identifying linkage to chromosome 13q may be informative in identifying suicide risk early and prevent morbidity and mortality in schizophrenia patients.

Increased risk of suicide in schizophrenia patients with linkage to chromosome 13q

A highly specific pattern of volumetric brain changes due to 22q11.2 deletions in both mice and humans

A highly specific pattern of volumetric brain changes due to 22q11.2 deletions in both mice and humans.

Abstract Background Schizophrenia is a heterogeneous group of disorders. The familial-sporadic distinction has been considered under a range of genetic models. Research supports a strong association of de novo copy mutations with sporadic schizophrenia. The aim of the study was to determine a more homogenous phenotype for genetic research via comparison of various clinical and socio-demographic variables in familial and sporadic schizophrenia. Methods A cross-sectional observational design was used. This study included 384 participants with schizophrenia/schizoaffective disorder from an Afrikaner founder population in South Africa that previously participated in genetic research. A comprehensive data capturing sheet was completed from a pre-existing database that contains information obtained from the Diagnostic Interview for Genetic Studies, chronological clinical summary reports and additional sources of information. The study protocol was approved by the Research Ethics Committee from the Faculty of Health Sciences at the University of Pretoria. Logit models were fitted using the backward elimination procedure to investigate relationships where the dependent variable was binary. Odds ratio estimates were calculated for independent variables that were significant in the model. The Kruskal-Wallis test was conducted to compare the means of groups. For cases where there were significant differences a post-hoc test with a Bonferroni correction was done to determine which groups differ significantly. Results There were 214 familial and 170 sporadic subjects. 279 had a diagnosis of schizophrenia, 66 schizoaffective, bipolar type and 39 schizoaffective disorder, depressive type. 242 were male and 142 female. The age at onset of the primary psychiatric diagnosis, season of birth, co-morbid diagnoses, symptomatology, suicidality history and marital status weren’t significantly different when considering the combined schizophrenia/schizoaffective disorder group and its relationship to familiality. Early deviant behaviour was however decreased in the sporadic group. These findings were replicated when analysing schizophrenia independently from schizoaffective disorder. The sporadic schizoaffective disorder, bipolar type did however have a significantly lower age at onset (mean 20.18 versus 25.07 years), 8.8 times more hallucinations, 6.6 times more odd behaviour before the age of 10 and were 2.8 times more likely to be single. The bipolar type also had 2.9 times more suicide attempts as opposed to ideation. This finding wasn’t statistically significant. The sporadic schizoaffective group overall was 2.2 times more likely to abuse substances. The depressive type didn’t differ significantly with regards to age at onset, season of birth, co-morbidities, early deviant behaviour, symptomatology, suicidality or marital status. Discussion The combined schizophrenia/schizoaffective group didn’t differ significantly, nor did schizophrenia and schizoaffective disorder depressive type when analysed independently. The sporadic schizoaffective bipolar type differed significantly on multiple important variables that suggest a poorer prognosis and increased disease severity. The sporadic schizoaffective bipolar type forms a more homogenous group, with genetic studies hinting at relatively specific genetic risk factors. Studies elucidating the genetic architecture of this group could prove invaluable in clarifying the aetiology of schizophrenia.

S189. carving a more specific subtype of schizophrenia for genetic studies: sporadic schizoaffective bipolar type

Objective : To determine and compare the incidence of early non-psychotic deviant behaviour (i.e. under the age of ten) in Afrikaner patients with bipolar disorder, schizo-affective disorder and schizophrenia.
Methods : Patients with bipolar disorder, schizo-affective disorder and schizophrenia were interviewed using a structured questionnaire probing for early deviant childhood behaviour starting before the age of 10 years. Information from close family members was also obtained where possible. Seven areas of possible deviance were probed into: social dysfunction, unprovoked aggression, extreme anxiety, chronic sadness, extreme odd behaviours, attention impairment and learning difficulties. Demographic data included: age, marital status, gender, and years of formal education. The following clinical features were also recorded: age of onset of illness and suicide attempts.
Results : A total of 74 patients diagnosed with bipolar disorder, 43 patients diagnosed with schizo-affective disorder and 80 patients diagnosed with schizophrenia were interviewed. Early deviant behaviour was statistically more prevalent in schizophrenia (65%) and schizo-affective disorder (60, 5%), than in the bipolar group (21, 6%). Deviant childhood behaviour was grouped into 3 clusters: social functioning impairment cluster (social isolation, aggression, extreme odd behavior), mood/anxiety cluster (extreme fears, chronic sadness) and a cognitive impairment cluster (attention impairment, learning disability). Bipolar patients showed significantly less social functioning and cognitive impairment compared to patients with schizo-affective disorder and schizophrenia.
Conclusion : Our findings suggest that early deviant behaviour may be a possible endophenotypic marker in schizophrenia and schizoaffective disorder.

Maria Karayiorgou

Papers

Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency

Increased risk of suicide in schizophrenia patients with linkage to chromosome 13q

A highly specific pattern of volumetric brain changes due to 22q11.2 deletions in both mice and humans.

S189. carving a more specific subtype of schizophrenia for genetic studies: sporadic schizoaffective bipolar type

Early non-psychotic deviant behaviour as an endophenotypic marker in bipolar disorder, schizo-affective disorder and schizophrenia : original article