The polygenic architecture of schizophrenia — rethinking pathogenesis and nosology

Abstract

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, behavioural 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.

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Fig. 1: The aetiology of schizophrenia and its relationship to other psychiatric disorders.
Fig. 2: A comparison of genetic overlap and genetic correlation.
Fig. 3: The proportions of causal variants shared between schizophrenia and other phenotypes.
Fig. 4: Statistical power calculations for current and future GWAS.

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Acknowledgements

The authors’ research is supported by National Institutes of Health (NIH) grants NS057198 and EB00790 and NIH National Institute on Drug Abuse (NIDA)/National Cancer Institute (NCI) grant U24DA041123 to A.M.D; and Research Council of Norway grants 229129, 213837, 248778, 223273 and 249711, South-East Norway Regional Health Authority grant 2017-112, and funding from K.G. Jebsen Stiftelsen (SKGJ) to O.A.A. The authors also thank N. Karadag for preparation of the original artwork for figure 2.

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O.A.A., O.B.S., O.F. and A.M.D. researched data for the article, contributed substantially to discussions of its content and participated in review or editing of the manuscript before submission. In addition, O.A.A. and O.B.S. wrote the initial draft.

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Correspondence to Ole A. Andreassen.

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O.A.A. declares that he has received a speaker’s honorarium from Lundbeck and is a consultant for HealthLytix. A.M.D. declares that he is a founder of and holds equity interest in CorTechs Labs, that he is a member of the scientific advisory boards of CorTechs Labs and HealthLytix, and receives research funding from General Electric Healthcare. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. The other authors declare no competing interests.

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Related links

Conditional false discovery rate (FDR) software: https://github.com/precimed/pleiofdr

MiXeR software: https://github.com/precimed/mixer.

Glossary

Polygenic risk score

(PRS). An estimate of overall genetic propensity to develop a given phenotype, derived from the sum of a given individual’s risk alleles weighted by their effect sizes.

SNP-based heritability

The fraction of phenotypic variation attributable to common genetic variants detected in genome-wide association studies. Heritability of continuous traits (such as height) is estimated by comparison with the observed range (observed scale), whereas heritability of binary traits (such as schizophrenia) is estimated as a propensity score that takes into account population prevalence (liability scale).

Linkage disequilibrium

The tendency for genes, alleles or other genetic markers to be non-randomly inherited in association with each other owing to physical proximity to one another on the same chromosome.

Genetic pleiotropy

A genetic variant that affects more than one phenotype.

Protein isoform

Many human genes encode multiple protein variants generated by alternative promoters, alternative mRNA splicing or post-translational modification.

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Smeland, O.B., Frei, O., Dale, A.M. et al. The polygenic architecture of schizophrenia — rethinking pathogenesis and nosology. Nat Rev Neurol 16, 366–379 (2020). https://doi.org/10.1038/s41582-020-0364-0

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