The discovery of integrated gene networks for autism and related disorders

Fereydoun Hormozdiari, Osnat Penn, Elhanan Borenstein, Evan E. Eichler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Despite considerable genetic heterogeneity underlying neurodevelopmental diseases, there is compelling evidence that many disease genes will map to a much smaller number of biological subnetworks. We developed a computational method, termed MAGI (merging affected genes into integrated networks), that simultaneously integrates protein-protein interactions and RNA-seq expression profiles during brain development to discover "modules" enriched for de novo mutations in probands. We applied this method to recent exome sequencing of 1116 patients with autism and intellectual disability, discovering two distinct modules that differ in their properties and associated phenotypes. The first module consists of 80 genes associated with Wnt, Notch, SWI/SNF, and NCOR complexes and shows the highest expression early during embryonic development (8-16 post-conception weeks [pcw]). The second module consists of 24 genes associated with synaptic function, including long-term potentiation and calcium signaling with higher levels of postnatal expression. Patients with de novo mutations in these modules are more significantly intellectually impaired and carry more severe missense mutations when compared to probands with de novo mutations outside of these modules. We used our approach to define subsets of the network associated with higher functioning autism as well as greater severity with respect to IQ. Finally, we applied MAGI independently to epilepsy and schizophrenia exome sequencing cohorts and found significant overlap as well as expansion of these modules, suggesting a core set of integrated neurodevelopmental networks common to seemingly diverse human diseases.

Original languageEnglish
Pages (from-to)142-154
Number of pages13
JournalGenome Research
Issue number1
StatePublished - 1 Jan 2015
Externally publishedYes


FundersFunder number
National Institutes of Health
National Institute of Mental HealthR01MH101221


    Dive into the research topics of 'The discovery of integrated gene networks for autism and related disorders'. Together they form a unique fingerprint.

    Cite this