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Genomics of schizophrenia, bipolar disorder and major depressive disorder

Nature Reviews Genetics volume 26, pages 862–877 (2025)Cite this article

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Abstract

Schizophrenia, bipolar disorder and major depressive disorder — which are the most common adult disorders requiring psychiatric care — contribute substantially to premature mortality and morbidity globally. Treatments for these disorders are suboptimal, there are no diagnostic pathologies or biomarkers and their pathophysiologies are poorly understood. Novel therapeutic and diagnostic approaches are thus badly needed. Given the high heritability of psychiatric disorders, psychiatry has potentially much to gain from the application of genomics to identify molecular risk mechanisms and to improve diagnosis. Recent large-scale, genome-wide association studies and sequencing studies, together with advances in functional genomics, have begun to illuminate the genetic architectures of schizophrenia, bipolar disorder and major depressive disorder and to identify potential biological mechanisms. Genomic findings also point to the aetiological relationships between different diagnoses and to the relationships between adult psychiatric disorders and childhood neurodevelopmental conditions.

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Fig. 1: Summary of genomic findings for schizophrenia, bipolar disorder and depression.
Fig. 2: Genetic correlations and impact of minimal phenotyping, and the neurodevelopmental continuum and gradient.
Fig. 3: Neuroanatomical and cellular enrichment of common variant liability to schizophrenia based on gene expression specificity.

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Acknowledgements

The authors thank S. Legge and S. Lock for creating the original version of Fig. 1a and Y. Baran for creating the original version of Fig. 3.

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Authors and Affiliations

  1. Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK

    Michael J. Owen, Nicholas J. Bray, James T. R. Walters & Michael C. O’Donovan

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  1. Michael J. Owen
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  2. Nicholas J. Bray
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  3. James T. R. Walters
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  4. Michael C. O’Donovan
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The authors contributed equally to all aspects of the article.

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Correspondence to Michael J. Owen.

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Competing interests

All authors receive grants from the Takeda Pharmaceutical Company Ltd, outside of the submitted work. M.J.O., J.T.R.W. and M.C.O’D. received grants from Akrivia Health, outside the submitted work. Takeda and Akrivia had no involvement in the conception, design, implementation or interpretation of this Review.

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Related links

Depression Genetics in Africa: https://wellcome.org/grant-funding/people-and-projects/grants-awarded/depression-genetics-africa-depgenafrica

Latin American Genomics Consortium: https://www.latinamericangenomicsconsortium.org/

Neuropsychiatric Genetics in African Populations: https://www.broadinstitute.org/stanley-centre-psychiatric-research/stanley-global/neuropsychiatric-genetics-african-populations-neurogap

Glossary

Burden test

Frequently used to increase the power of exome-wide association studies. They combine sets of variants within a gene to produce a single burden score that is then tested for association.

Common variants

Variants that are present in the population at frequencies of 1% or more. They include single-nucleotide polymorphisms, which can be assayed in parallel across the genome in genome-wide association studies.

Copy number variants

(CNVs). Variants for which the number of copies of a specific segment of DNA varies in the population. These structural differences between individuals may have arisen as a result of duplications, deletions or other changes.

Delusion

A fixed, false belief that is not amenable to change despite conflicting evidence.

Depression

A mental state that involves low mood and decreased activity.

Genetic correlation

(rg). An estimate of the average similarity of causal allelic effects on two traits. This usually refers to the genome-wide average, although it can be specified to be locus wide or chromosome wide. A high degree of genetic correlation is usually indicative of pleiotropy.

Hallucination

A perception in the absence of an external stimulus that has a compelling sense of reality.

Hypomania

A less severe form of mania that is not accompanied by marked functional impairments (for example, to occupation or personal relationships).

Loss-of-function mutation-intolerant genes

Genes with near-complete depletion of protein-truncating variants in population studies, suggesting that there is strong direct selection against such variants.

Mania

A mental state that involves elevated mood, which can be euphoric or irritable, and increased activity.

Mood-incongruent psychotic symptoms

Hallucinations or delusions that are not aligned with the person’s current mood state.

Pleiotropy

Describes the phenomenon whereby a variant or gene influences more than one phenotype. The terms ‘direct’, ‘horizontal’ and ‘biological’ pleiotropy imply that the effects on the phenotypes are independent. The terms ‘mediated’, ‘vertical’ and ‘indirect’ pleiotropy imply that the effects on one phenotype are mediated through the other; for example, alleles that influence smoking behaviour are likely to have pleiotropic effects on all traits for which smoking is a risk factor.

Polygenic risk score

(PRS). Summarizes the estimated effect of many genetic variants on an individual’s phenotype. It is typically calculated as a weighted sum of trait-associated alleles.

Protein-truncating variants

(PTVs). Variants that are predicted to shorten the coding sequence of a gene and which may result in reduced expression of that gene and its protein owing to nonsense-mediated decay. They include nonsense, frameshift and essential splice site variants.

Psychotic symptoms

Symptoms, particularly delusions and hallucinations, that involve difficulty in determining what is real from what is not.

Rare coding variants

(RCVs). Variants in the coding sequence of a gene that are present in less than 1% of the population. They can be detected by genome-wide sequencing studies.

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Owen, M.J., Bray, N.J., Walters, J.T.R. et al. Genomics of schizophrenia, bipolar disorder and major depressive disorder. Nat Rev Genet 26, 862–877 (2025). https://doi.org/10.1038/s41576-025-00843-0

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