Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience (Willsey et al., Neuron, 2021)

Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.

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Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci (Sanders et al., Neuron, 2015)
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Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2 (Hoffman et al., Neuron, 2016)

Fish carrying homozygous mutations in the ASD-associated gene CNTNAP2 have fewer GABAergic neurons and are sensitive to drug-induced seizures. High throughput behavioral screening identifies night time hyperactivity in these fish. Pharmacological screening identifies estrogens as causing the opposite behavioral response, and estrogens can suppress the night time hyperactivity of CNTNAP2 fish. This work highlights the utility of the fish model for identifying new pharmacological pathways relevant to ASD.

De Novo Coding Variants Are Strongly Associated with Tourette Disorder (Willsey et al., Neuron, 2017)

Exome sequencing on 511 trios from the Tourette International Collaborative Genetics cohort and the Tourette Syndrome Association International Consortium on Genetics showed strong and consistent evidence for the contribution of de novo likely gene-disrupting variants. Four likely risk genes with multiple de novo damaging variants are recurrent in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. In addition to clarifying the genetic architecture of TD, these results demonstrate a reliable path forward for systematic gene discovery in TD, as has been shown for other neurodevelopmental disorders.

The contribution of de novo coding mutations to autism spectrum disorder (Iossifov et al., Nature, 2014)

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.