“The Polygenic Architecture of Schizophrenia—Rethinking Pathogenesis and Nosology”, 2020-06-11 (; similar):
Schizophrenia is a severe psychiatric disorder with considerable morbidity and mortality. Although the past two decades have seen limited improvement in the treatment of schizophrenia, research into the genetic causes of this condition has made important advances that offer new insights into the aetiology of schizophrenia. This Review summarizes the evidence for a polygenic architecture of schizophrenia that involves a large number of risk alleles across the whole range of population frequencies. These genetic risk loci implicate biological processes related to neurodevelopment, neuronal excitability, synaptic function and the immune system in the pathogenesis of schizophrenia. Mathematical models also suggest a substantial overlap between schizophrenia and psychiatric, behavioral and cognitive traits, a situation that has implications for understanding its clinical epidemiology, psychiatric nosology and pathobiology. Looking ahead, further genetic discoveries are expected to lead to clinically relevant predictive approaches for identifying high-risk individuals, improved diagnostic accuracy, increased yield from drug development programmes and improved stratification strategies to address the heterogeneous disease course and treatment responses observed among affected patients.
Key points:
Schizophrenia is characterized by ‘positive’ psychotic symptoms (including hallucinations and delusions) and ‘negative’ symptoms (including blunted affect, apathy and social impairment); this disorder is associated with considerable morbidity and mortality.
In the past decade, important advances have been made in our understanding of the genetics of schizophrenia.
The polygenic architecture of schizophrenia is accounted for by thousands of common genetic variants with small effect sizes and a few rare variants with large effect sizes.
These genetic risk variants implicate dysregulation of biological processes linked to neurodevelopment, neuronal excitability, synaptic function and the immune system in schizophrenia.
Genetic risk factors associated with schizophrenia transcend diagnostic boundaries and form a continuum with normal psychosocial traits, which challenges current psychiatric nosology.
Although increasingly larger sample sizes will accelerate the discovery of genetic variants, novel statistical methodologies could also improve the efficiency of analyses, render discoveries clinically relevant and facilitate precision medicine approaches.