Genetic architecture of schizophrenia: a review of major advancements.

Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

Association of smoked cannabis with treatment resistance in schizophrenia.

Association of cannabis use with schizophrenia is a well-established finding. Its role in causation, however, is debated. Different studies have found that cannabis use impacts the outcome of schizophrenia and is associated with treatment non-adherence and a higher rate of relapses. In this paper, we investigated the impact of self-reported cannabis use on treatment response in a cohort of schizophrenia patients from Pakistan, a middle-income country. The data was collected from a psychiatric hospital in Khyber Pakhtunkhwa province of Pakistan where cannabis use is prevalent. Clinical evaluation and therapeutic response were established using the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impressions Scales-Severity (CGI-S) and Improvement (CGI-I) scale. Lack of response to adequate treatment with two trials of antipsychotics was classed as treatment resistance. We compared the treatment-resistant and treatment responsive groups for different variables including cannabis use, age at onset of illness, duration of untreated psychosis and consanguinity. We had data on 230 patients. More than ninety percent of our participants were men. The rate of treatment resistance was over 60%. Ongoing use of cannabis had an association with treatment resistance. We only included cases where treatment adherence was not a problem.