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The discovery of integrated gene networks for autism and related disorders
Open accessAbstract
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 (m erging a ffected g enes into i ntegrated 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.
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“M1 consists of 47 genes associated with Wnt, Notch, SWI/SNF, and NCOR signaling, and showing high expression during embryonic development (8–16 pcw) (Fig. 1, Supplementary Table S1).”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [29]
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“M2 includes 21 genes associated with synaptic function and mainly expressed at postnatal stages (Fig. 1, Supplementary Table S1).”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [29]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These modules were built through the exome sequencing data of 1116 patients affected by ASD and ID29.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [29]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We focused in particular on 68 genes which, despite not being an exhaustive catalog of genetic risk loci for ASD and ID, were previously shown to represent functional modules enriched of de novo mutations in probands29.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [29]
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“Module 1 includes genes associated to transcriptional regulation during brain development, whereas module 2 is composed of synaptic genes involved in long-term potentiation and calcium signaling29.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [29]
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“Module 1 includes genes associated to transcriptional regulation during brain development, whereas module 2 is composed of synaptic genes involved in long-term potentiation and calcium signaling29.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [29]
In the citing paper
“MAGI identified modules containing functionally related genes enriched for deleterious mutations in ASD, many of which are under strong purifying selection, and are also found in epilepsy, schizophrenia and intellectual disability133.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [133]
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Metadata
- Authors
- Hormozdiari, F., Penn, O., Borenstein, E., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2014-11-05
- Volume
- 25
- Issue
- 1
- Pages
- 142-154
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC4317170
- OpenAlex
- W2106870542
- Cited by
- 249
- References
- 53
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 11 · 2023: 16 · 2022: 20 · 2021: 20 · 2020: 29 · 2019: 27 · 2018: 23 · 2017: 27 · 2016: 43 · 2015: 16 · 2014: 1
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- Funders
- Simons Foundation (303241)
- NIH/NIMH (R01MH101221)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- autism spectrum disorder, intellectual disability, de novo mutations, gene regulatory networks, Three Kings, protein-protein interaction, RNA-seq expression, brain development, Wnt signaling, Notch signaling, SWI/SNF complex, synaptic function, long-term potentiation, calcium signaling, epilepsy, schizophrenia, neurodevelopmental disorders, missense mutations, disease severity
- MeSH terms
- Algorithms, Autistic Disorder, Epilepsy, Humans, Phenotype, Schizophrenia, Cohort Studies, Cluster Analysis, Databases, Factual, Sequence Analysis, RNA, Genetic Heterogeneity, Mutation, Missense, Gene Regulatory Networks, Exome
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