Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

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Biological insights from 108 schizophrenia-associated genetic loci

Prospective Cohort Study

/pdf/research-domain-criteria-rdoc-toward-a-new-classification-59j2rllxst.pdf

Research domain criteria (RDoC): toward a new classification framework for research on mental disorders

Background 
The quality and quantity of individuals' social relationships has been linked not only to mental health but also to both morbidity and mortality.
Objectives 
This meta-analytic review was conducted to determine the extent to which social relationships influence risk for mortality, which aspects of social relationships are most highly predictive, and which factors may moderate the risk.
Data Extraction 
Data were extracted on several participant characteristics, including cause of mortality, initial health status, and pre-existing health conditions, as well as on study characteristics, including length of follow-up and type of assessment of social relationships.
Results 
Across 148 studies (308,849 participants), the random effects weighted average effect size was OR = 1.50 (95% CI 1.42 to 1.59), indicating a 50% increased likelihood of survival for participants with stronger social relationships. This finding remained consistent across age, sex, initial health status, cause of death, and follow-up period. Significant differences were found across the type of social measurement evaluated (p<0.001); the association was strongest for complex measures of social integration (OR = 1.91; 95% CI 1.63 to 2.23) and lowest for binary indicators of residential status (living alone versus with others) (OR = 1.19; 95% CI 0.99 to 1.44).
Conclusions 
The influence of social relationships on risk for mortality is comparable with well-established risk factors for mortality.

Please see later in the article for the Editors' Summary

/pdf/social-relationships-and-mortality-risk-a-meta-analytic-2ghmxi4ksm.pdf

Social Relationships and Mortality Risk: A Meta-analytic Review

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases. A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

/pdf/the-mutational-constraint-spectrum-quantified-from-variation-2e87wuiyb1.pdf

The mutational constraint spectrum quantified from variation in 141,456 humans

OBJECTIVE
Increasing rates of caesarean sections has led to concerns about long-term effects on the offspring's health, and it has been hypothesised that caesarean section induced differences in the child's microbiota could potentially increase the risk of mental disorders.


METHODS
Nationwide Danish cohort study of 2,196,687 births was conducted between 1980 and 2015, with 38.5 million observation-years. Exposure was 'Caesarean Section' and outcome was the child's risk of any mental disorder. Absolute and relative risks (RRs) were estimated using inverse probability weighting to adjust for age, calendar time and confounding variables while accounting for the competing risk of death.


RESULTS
Caesarean section (n = 364,908, 16.6%), compared to vaginal birth, was associated with a small RR increase of 8% (RR, 1.08; 95% CI, 1.04-1.13; n = 44,352) for the development of any in-patient psychiatric admission at age 36 for the offspring and with a small absolute risk difference of 0.47% (95% CI, 0.23-0.76). When looking at all in-patient, out-patient and emergency room psychiatric contacts among people born after 1995, the effect was diminished (RR, 1.04; 95% CI, 0.99-1.09; n = 15,211). The risk was comparable when comparing prelabour versus intrapartum caesarean section (RR, 0.98; 95% CI, 0.90-1.08) and acute versus planned caesarean section (RR, 1.00; 95% CI, 0.80-1.29).


CONCLUSION
Birth by caesarean section was associated with only a very slightly increased risk of any in-patient psychiatric admission for the offspring and diminished even further when including all psychiatric contacts. The very small associations observed may be explained by unmeasured confounding and is unlikely to be of substantial clinical relevance.

Effect of mode of birth on development of mental disorders in the offspring.

Sleep disturbances and the association with attenuated psychotic symptoms in individuals at ultra high-risk of psychosis.

Predictors of Mortality Following a Schizophrenia Spectrum Diagnosis: Evidence from the 20-Year Follow-Up of the OPUS Randomized Controlled Trial

Predictors of transfer and prognosis after transfer from child and adolescent mental health services to adult mental health services—a Danish nationwide prospective register-based cohort study

ED FROM Baker AL, Hides L, Lubman DI. Treatment of cannabis use among people with psychotic or depressive disorders: a systematic review. J Clin Psychiatry 2010;71:247–54. Correspondence to: Dr Amanda L Baker, Centre for Brain and Mental Health Research, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; amanda.baker@newcastle.edu.au Sources of funding: National Health and Medical Research Council and the Colonial Foundation.

Merete Nordentoft

Papers

Effect of mode of birth on development of mental disorders in the offspring.

Sleep disturbances and the association with attenuated psychotic symptoms in individuals at ultra high-risk of psychosis.

Predictors of Mortality Following a Schizophrenia Spectrum Diagnosis: Evidence from the 20-Year Follow-Up of the OPUS Randomized Controlled Trial

Predictors of transfer and prognosis after transfer from child and adolescent mental health services to adult mental health services—a Danish nationwide prospective register-based cohort study

Review: pharmacological and psychological interventions decrease cannabis use in people with depressive and psychotic disorders in the short term.