Genetic insights into the neurodevelopmental origins of schizophrenia

Key Points

  • Schizophrenia is a severe neuropsychiatric disorder with an unknown causative pathophysiology.

  • Genome-wide association studies applied to schizophrenia have successfully identified discrete risk variants of common and rare frequency, but the functional characterization and neurobiological import of these loci remain to be elucidated.

  • The neurodevelopmental model provides a translational context for schizophrenia genetics, positing that schizophrenia genetic and epigenetic risk factors converge on early brain development to perturb neurodevelopmental trajectories.

  • Post-mortem studies of brain gene expression and DNA methylation suggest that risk factors for schizophrenia, both genetic and epigenetic variations that leave marks in the adult brain, occur principally during early brain development rather than during the tumultuous period of late adolescence or early adulthood, when the diagnosis is typically made.

  • The diverse and protean effects of genetic and epigenetic risk of schizophrenia on brain development may be parsimoniously conceptualized as introducing developmental 'noise' — various subtle perturbations, including those to early brain circuits and synaptic organization — analogous to alterations in autism and intellectual disability but with lesser 'noise' burden or more amenable to compensation.

  • Schizophrenia risk loci should be functionally characterized (spatially and temporally) in relevant neurodevelopmental models, including post-mortem brain across developmental stages and placenta and stem cell models.

Abstract

Schizophrenia is a severe neuropsychiatric disorder with a longstanding history of neurobiological investigation. Although the underlying causal mechanisms remain unknown, early neurodevelopmental events have been implicated in pathogenesis, initially by epidemiological and circumstantial data but more recently by brain-specific molecular and genetic findings. Notably, genomic research has recently uncovered discrete risk variants and risk loci associated with schizophrenia, with the potential to elucidate disease mechanisms. This Review revisits the neurodevelopmental model of schizophrenia from a current genetics perspective, delineating the complex genetic basis of the disorder and highlighting gene expression and epigenetic analyses of post-mortem cortical tissue that suggest that early brain development mediates genetic risk associated with schizophrenia. Future functional genomics investigations will accordingly need to characterize schizophrenia risk loci in relevant neurodevelopmental models.

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Figure 1: Genetic and epigenetic risk factors for schizophrenia converge on neurodevelopment.

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Acknowledgements

The authors are grateful to A. Jaffe and R. Straub for their constructive comments regarding the manuscript and the data reviewed. The authors are also indebted to T. Hyde and J. Kleinman for their many contributions to the ideas expressed.

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R.B. and D.R.W. contributed equally to researching data for the article, discussion of content, writing and review and editing of the manuscript before submission.

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Correspondence to Daniel R. Weinberger.

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Glossary

Neural patterning

The process by which cells in the developing nervous system acquire distinct identities according to their specific spatial positions. Controlled by combinatorial action of signalling gradients.

Complex diseases

Diseases caused by a combination of multiple genetic and environmental factors. Examples include cardiovascular disease, type 2 diabetes, autoimmune diseases, cancer, psychiatric disorders and Alzheimer disease.

Single-nucleotide polymorphisms

(SNPs). Variations in a single nucleotide that occurs at a specific position in the genome. The prevalence of any given SNP may be estimated with population-specific reference panels.

Liability scale

The contribution of genetic loci to disease, assuming that individuals have a latent continuous liability of risk of disease that reflects genetic and non-genetic risk factors.

Polygenic risk score

A number based on variation in multiple genetic loci, calculated for a specific individual by summing trait-associated alleles weighted by their estimated effect sizes.

Copy number variants

(CNVs). Structural variations, deletions or duplications of chromosomal segments, typically greater than 1 kb in length, that may affect one or multiple genes, potentially with resulting gene-dosage effects.

Penetrance

The proportion of individuals who harbour a particular variant (or genotype) that express the associated trait or, if a disease-causing mutation, that exhibit clinical symptoms.

Tandem repeat polymorphisms

Variable-number repeat-containing elements or DNA motifs in which one or more nucleotides are repeated directly in adjacency, such as the tri-nucleotide CAG repeats in the gene encoding huntingtin.

Epistatic networks

Networks of non-additive interactions between genotypes at two (or more) loci.

Linkage disequilibrium

(LD). The nonrandom association of alleles at different loci — that is, higher or lower association than if the loci were independent and associated randomly.

Gene set enrichment analyses

An analytic approach to identify classes of genes that are statistically over-represented in a large set of genes and may have an association with a phenotype of interest.

Gene set burden test

An association method of grouping or aggregating variants likely to have similar function instead of testing variants individually.

Expression quantitative trait loci

(eQTLs). Genomic loci or variants that contribute to variation in gene expression levels at proximal or distal loci.

Next-generation RNA sequencing

RNA sequencing that measures the quantity of RNA in a biological sample at a given moment in time, facilitating assessment of gene or transcript differences over time or between groups.

DNA methylation quantitative trait loci

(mQTLs). CpG or other methylation sites in which changes in DNA methylation are associated with a DNA variant at proximal or distal loci.

Induced pluripotent stem cells

(iPSCs). Pluripotent stem cells that are generated by directly reprogramming adult cells and that can be differentiated into specialized cell types while maintaining the genetic background of the individual of origin.

Somatic mosaic events

Within one individual, the presence of two or more cell populations with different genotypes, derived from a post-zygotic mutation, ranging from single-nucleotide to large segmental variations.

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Birnbaum, R., Weinberger, D. Genetic insights into the neurodevelopmental origins of schizophrenia. Nat Rev Neurosci 18, 727–740 (2017). https://doi.org/10.1038/nrn.2017.125

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