Hundreds of different genes have been linked to autism – but a new study suggests it may be their path to the brain that matters

Good news!

"... The researchers found that these genes “converge” on a shared set of biological pathways in the brain, triggering similar downstream effects as brain cells mature. ...

Using a CRISPR gene-editing tool, they switched off 23 genes associated with neurodevelopmental disorders in human brain cells. They then tracked how each genetic disruption altered gene activity across different stages of brain development.

Critically, they found that many of the at-risk genes produced similar effects downstream as brain cells matured. But they first converged in the same neural pathways, including pathways involved in synaptic communication, regulation of gene expression, and mitochondrial function ..."

From the abstract:

"Diverse risk genes have been identified for neurodevelopmental disorders (NDDs), but how these genes converge on similar biological pathways in neurons, and thus give rise to similar phenotypes, is unclear.

Here we apply a pooled CRISPR approach to successfully target 23 NDD loss-of-function genes with roles in chromatin biology and examine convergent effects on gene expression across human induced pluripotent stem cell-derived neural progenitor cells, glutamatergic neurons and GABAergic neurons.

Points of convergence vary between these cell types, with the greatest number of convergent genes and strongest convergent networks in mature glutamatergic neurons, where they broadly represent synaptic, epigenetic and, unexpectedly, mitochondrial pathways.

The most convergent networks were observed between NDD genes with shared biological annotations, clinical associations and co-expression patterns in human post-mortem brain.

Drugs that were predicted to reverse convergent transcriptomic signatures and/or arousal and sensory processing behaviors ameliorated behavioral phenotypes in zebrafish NDD gene mutants.

These results suggest that convergent effects of NDD risk genes could provide clinically useful insights."

Many genes have been linked to autism – but a new study suggests it may be their path to the brain that matters | Yale News "While scientists have identified hundreds of different genes that are associated with autism, a new Yale-led study suggests that the specific genes may be less important than the pathway they take to the brain."

Transcriptomic and phenotypic convergence of neurodevelopmental disorder risk genes in vitro and in vivo

Fig. 1: KO [knock out] effects of 21 NDD risk genes are most strongly correlated in mature neurons.

Fig. 2: Gene-level convergence is greatest in mature glutamatergic neurons.

Fig. 3: Network-level convergence resolves cell-type-specific and developmental-specific node genes.

Fig. 4: Functional similarity and brain co-expression between NDD genes predict gene-level and network-level convergence, with unique influences by cell type.