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Genomics, convergent neuroscience and progress in understanding autism spectrum disorder

Nature Reviews Neuroscience volume 23, pages 323–341 (2022)Cite this article

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Abstract

More than a hundred genes have been identified that, when disrupted, impart large risk for autism spectrum disorder (ASD). Current knowledge about the encoded proteins — although incomplete — points to a very wide range of developmentally dynamic and diverse biological processes. Moreover, the core symptoms of ASD involve distinctly human characteristics, presenting challenges to interpreting evolutionarily distant model systems. Indeed, despite a decade of striking progress in gene discovery, an actionable understanding of pathobiology remains elusive. Increasingly, convergent neuroscience approaches have been recognized as an important complement to traditional uses of genetics to illuminate the biology of human disorders. These methods seek to identify intersection among molecular-level, cellular-level and circuit-level functions across multiple risk genes and have highlighted developing excitatory neurons in the human mid-gestational prefrontal cortex as an important pathobiological nexus in ASD. In addition, neurogenesis, chromatin modification and synaptic function have emerged as key potential mediators of genetic vulnerability. The continued expansion of foundational ‘omics’ data sets, the application of higher-throughput model systems and incorporating developmental trajectories and sex differences into future analyses will refine and extend these results. Ultimately, a systems-level understanding of ASD genetic risk holds promise for clarifying pathobiology and advancing therapeutics.

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Fig. 1: Relationship between effect size and allele frequency for loci discovered in autism spectrum disorder or schizophrenia.
Fig. 2: Emerging patterns of ASD convergence identified from gene expression data.

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Acknowledgements

The authors thank S. Wang for data analysis and graphical representation for Fig. 1 and S. Pyle for graphic design. This work was supported by a gift from the Overlook International Foundation and grant support from the National Institutes of Mental Health (NIMH) (U01MH116487, R01MH115963, 1U01MH115747, R25MH06048) and the Psychiatric Cell Map Initiative (pcmi.ucsf.edu).

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Author notes

  1. These authors contributed equally: Helen Rankin Willsey, A. Jeremy Willsey.

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA

    Helen Rankin Willsey, A. Jeremy Willsey, Belinda Wang & Matthew W. State

  2. Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA, USA

    A. Jeremy Willsey & Matthew W. State

  3. Langley Porter Psychiatric Institute, University of California, San Francisco, San Francisco, CA, USA

    Belinda Wang & Matthew W. State

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  1. Helen Rankin Willsey
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Related links

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Glossary

Autism spectrum disorder

(ASD). A group of developmental disorders characterized by deficits in social communication and social interaction, and restrictive and repetitive patterns of behaviour, interests or activities.

Intellectual disability

A developmental disorder characterized by deficits in intellectual functioning (including reasoning, problem-solving and academic learning) and adaptive functioning (including communication and independent living).

Genetic architecture

The characteristics of genetic variation that contribute to a specific phenotype, including variant frequency, effect size and their interaction with each other and the environment.

Locus heterogeneity

Variants at different gene loci result in a similar phenotype, individually (for monogenic diseases) or in combination (for complex traits).

Pleiotropy

A phenomenon in which a single gene contributes to multiple processes or phenotypic traits.

Convergent neuroscience

Studies that address the overlap, or intersection, of genetic risk for a psychiatric disorder with respect to molecular-level, cellular-level and circuit-level function as well as across multiple dimensions of analysis, including anatomical localization and developmental timing.

Gene Ontology terms

A hierarchical set of terms that aim to define the universe of possible descriptors a gene can have, including properties such as molecular function, cellular component and biological process.

Penetrance

The probability that an individual with a given genotype will exhibit the associated phenotype.

Resilience

The capacity of an individual to have a ‘better than expected outcome’ (for example, being unaffected despite having multiple autism spectrum disorder-associated genetic variants).

Protein-truncating variants

(Also referred to as loss-of-function or likely gene disrupting variants). Sequence variants that are predicted to shorten the protein-coding sequence of a gene — usually to the point of resulting in a non-functional protein or no protein at all due to nonsense-mediated decay — including nonsense, frameshift and essential splice site variants.

Somatic mutations

(Also known as mosaic mutations). Variants that are present in fewer than 100% of the cells of an individual (for example, present in brain cells but not present in germ-line cells), generally because the mutation occurred after fertilization.

Compound heterozygous variants

Variants similar to recessive variants, in that both alleles of a gene are mutated; however, in this case, the two alleles are different.

Neurodevelopmental disorders

(NDDs). A group of conditions (including autism spectrum disorder, attention deficit hyperactivity disorder, tic disorders and intellectual disability) characterized by developmental onset, atypical brain development and resultant impairments in cognition, communication, behaviour and/or motor skills.

Polygenic risk scores

Estimates of an individual’s genetic predisposition for a disorder or disease based on the collective effects of many genetic variants.

SFARI Gene

An evolving database compiled by the Simons Foundation Autism Research Initiative (SFARI) research program that includes a list of genes and copy number variants (CNVs) associated with autism spectrum disorder curated from human studies and animal models.

Missense variants

Single base-pair coding variants that result in altered amino acids, for which several metrics have been developed to predict the functional consequence, including the PolyPhen-2 (Polymorphism Phenotyping v2) and MPC (missense badness, PolyPhen-2 and constraint) metrics, for which a categorization of PolyPhen-2 missense 3 (Mis3) or an MPC score ≥2 reflects a probably damaging variant.

Gene Ontology enrichment analysis

A statistical approach that assesses whether specific Gene Ontology terms are statistically over-represented in a (generally large) set of genes or proteins (for example, among autism spectrum disorder risk genes).

Gene set enrichment analysis

Like Gene Ontology enrichment analysis, this statistical approach assesses whether specific Gene Ontology terms are statistically over-represented in a large set of genes or proteins; however, unlike Gene Ontology enrichment analysis, gene set enrichment analysis also incorporates the rank of genes within the set into the statistical test (for example, differentially expressed genes ranked based on the fold-change between cases and controls).

Pathway databases

Databases that annotate genes with an ontological approach to capture functional relationships, including molecular interactions, regulation and phenotype associations; common pathway databases include Gene Ontologies (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG).

Neurogenesis

The process by which new neurons are generated, in humans most active during gestational weeks 10–25.

BrainSpan Atlas of the Developing Human Brain

A foundational resource that includes bulk transcriptome profiling of up to 16 cortical and subcortical structures across human brain development (prenatal to adult).

Neurotypical

Description of individuals with apparently typical intellectual and cognitive development (for example, not affected by a neurodevelopmental or psychiatric disorder).

PsychENCODE

A consortium-based project that aims to produce multidimensional genomic data from human post-mortem brain tissue from neurotypical and patient donors to begin to functionally characterize risk variants in model systems, with an initial focus on autism spectrum disorder, bipolar disorder and schizophrenia.

Induced pluripotent stem cell

(iPSC). A pluripotent cell obtained by reprogramming somatic cells through ectopic expression of defined pluripotency factors and/or treatment with small molecules.

Organoids

(Also known as spheroids) 3D structures, derived in vitro from primary tissue, embryonic stem cells or induced pluripotent stem cells (iPSCs), that self-organize and recapitulate aspects of organ development, anatomy, cellular composition, physiology and function.

Gene modules

Typically, a set of genes with similar expression profiles that are inferred to be functionally related and co-regulated, and that can be identified through various module-detection methods (for example, gene co-expression).

Functional convergence

A situation in which seemingly disparate entities are associated with an overlapping function, which can occur at various levels of investigation, including molecular, cell taxonomic, morphological, neural circuit or phenotype level.

Sex differences

Differences between individuals of different sex in the same species, often including secondary sex characteristics, size and behavioural or cognitive traits.

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Willsey, H.R., Willsey, A.J., Wang, B. et al. Genomics, convergent neuroscience and progress in understanding autism spectrum disorder. Nat Rev Neurosci 23, 323–341 (2022). https://doi.org/10.1038/s41583-022-00576-7

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