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  • Review Article
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Schizophrenia genomics: genetic complexity and functional insights

Nature Reviews Neuroscience volume 25, pages 611–624 (2024)Cite this article

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Abstract

Determining the causes of schizophrenia has been a notoriously intractable problem, resistant to a multitude of investigative approaches over centuries. In recent decades, genomic studies have delivered hundreds of robust findings that implicate nearly 300 common genetic variants (via genome-wide association studies) and more than 20 rare variants (via whole-exome sequencing and copy number variant studies) as risk factors for schizophrenia. In parallel, functional genomic and neurobiological studies have provided exceptionally detailed information about the cellular composition of the brain and its interconnections in neurotypical individuals and, increasingly, in those with schizophrenia. Taken together, these results suggest unexpected complexity in the mechanisms that drive schizophrenia, pointing to the involvement of ensembles of genes (polygenicity) rather than single-gene causation. In this Review, we describe what we now know about the genetics of schizophrenia and consider the neurobiological implications of this information.

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Fig. 1: The allelic spectrum of schizophrenia.
Fig. 2: A pathway from genomics to an aetiological theory of schizophrenia.

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Acknowledgements

J.H.-L. was supported by the Swedish Research Council (Vetenskapsrådet, award 2018-00799), Swedish Brain Foundation (Hjärnfonden, award FO2018-0272) and European Research Council (SCHIZTYPE, grant agreement 819540). P.F.S. was supported by the Swedish Research Council (Vetenskapsrådet, award D0886501) and the US National Institute of Mental Health (R01s MH124871, MH121545 and MH123724).

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Authors and Affiliations

  1. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    Patrick F. Sullivan

  2. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    Patrick F. Sullivan

  3. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Patrick F. Sullivan & Shuyang Yao

  4. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Jens Hjerling-Leffler

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All authors researched data for the article and contributed substantially to discussion of the content. P.F.S. and J.H-L. wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Patrick F. Sullivan or Jens Hjerling-Leffler.

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P.F.S. is a consultant and shareholder for Neumora Therapeutics.

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Related links

Psychiatric Genetics Consortium: https://pgc.unc.edu/

Supplementary information

Glossary

Brain organoids

Three-dimensional cell cultures that mimic the structure and function of the brain, derived from pluripotent stem cells.

Copy number variants

(CNVs). Structural variations in the genome, in which large sections of DNA (containing from one gene to many genes) are duplicated or deleted, potentially influencing traits or diseases.

Dopamine hypothesis

A theory proposing that dysregulation of dopamine neurotransmission in the brain contributes to the development of schizophrenia.

Epigenomic

Referring to chemical modifications to DNA and histone proteins that regulate gene expression without altering the DNA sequence.

Genetic risk factors

Variations in the DNA sequence that increase the likelihood of developing a particular trait or disease (such as schizophrenia).

Genetic variants

Measurable differences in DNA sequence among individuals, including SNPs, coding and non-coding variants, copy number variants, insertion and deletions.

Genome-wide association study

(GWAS). A method to identify genetic variations across the entire genome associated with traits or diseases.

Heritability

The proportion of the total variation in a trait in a population that is owing to genetic differences among individuals.

Induced pluripotent stem cell

An adult cell reprogrammed to exhibit embryonic stem-cell-like properties and capable of differentiating into various cell types.

Linkage disequilibrium

The nonrandom association or correlation of alleles at different loci within a population. Linkage disequilibrium is detectible between pairs of genetic markers with tens of kilobases but may span many megabases in specific regions.

Mendelian randomization

A method using genetic variants as instrumental variables to investigate causal relationships between modifiable exposures and health outcomes.

Polygenic risk score

(PRS). A numerical score calculated from multiple genetic variants associated with a trait or disease, used as a summation of genetic predisposition of an individual.

Single-cell RNA sequencing

A sequencing technique to analyse gene expression in single cells (or single nuclei), providing insights into cellular heterogeneity and functional diversity.

SNPs

Variations in a single nucleotide at a specific position in the genome.

Whole-exome sequencing

(WES). Sequencing of the protein-coding regions of the genome.

Whole-genome sequencing

Sequencing of the entire genome, including coding and non-coding regions, providing a comprehensive view of the genetic makeup of an individual.

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Sullivan, P.F., Yao, S. & Hjerling-Leffler, J. Schizophrenia genomics: genetic complexity and functional insights. Nat. Rev. Neurosci. 25, 611–624 (2024). https://doi.org/10.1038/s41583-024-00837-7

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