The Roles of FMRP-Regulated Genes in Autism Spectrum Disorder: Single- and Multiple-Hit Genetic Etiologies
Open accessAbstract
Autism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental condition characterized by impairments in social interaction and communication and restricted and repetitive behaviors. Although roles for both de novo and familial genetic variation have been documented, the underlying disease mechanisms remain poorly elucidated. In this study, we defined and explored distinct etiologies of genetic variants that affect genes regulated by Fragile-X mental retardation protein (FMRP), thought to play a key role in neuroplasticity and neuronal translation, in ASD-affected individuals. In particular, we developed the Trend test, a pathway-association test that is able to robustly detect multiple-hit etiologies and is more powerful than existing approaches. Exploiting detailed spatiotemporal maps of gene expression within the human brain, we identified four discrete FMRP-target subpopulations that exhibit distinct functional biases and contribute to ASD via different types of genetic variation. We also demonstrated that FMRP target genes are more likely than other genes with similar expression patterns to contribute to disease. We developed the hypothesis that FMRP targets contribute to ASD via two distinct etiologies: (1) ultra-rare and highly penetrant single disruptions of embryonically upregulated FMRP targets ("single-hit etiology") or (2) the combination of multiple less penetrant disruptions of nonembryonic, synaptic FMRP targets ("multiple-hit etiology"). The Trend test provides rigorous support for a multiple-hit genetic etiology in a subset of autism cases and is easily extendible to combining information from multiple types of genetic variation (i.e., copy-number and exome variants), increasing its value to next-generation sequencing approaches.
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Steinberg et al. organized the FMRP target genes into distinct temporally expressed subpopulations affected by different classes of genetic variation associated with ASD.
“Recently, Steinberg et al. organized the FMRP target genes into distinct temporally expressed subpopulations affected by different classes of genetic variation associated with ASD36.”
From Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism (2014) · cites this paper as [36]
Steinberg et al. demonstrated that the 832 FMRP-interacting partners, particularly in two modules (FMRP 1 and FMRP 2), exhibit differential temporal expression: FMRP 1 genes tend to be upregulated during fetal development, whereas FMRP 2 genes are generally upregulated in adolescence and adulthood.
“In additionally, Steinberg et al.36 demonstrated that the 832 FMRP-interacting partners, particularly in two modules (represented as FMRP 1 and FMRP 2), exhibit differential temporal expression: genes in FMRP 1 tend to be specifically upregulated during fetal development, whereas genes in FMRP 2 were generally upregulated in adolescence and adulthood.”
From Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism (2014) · cites this paper as [36]
Other studies have also found that fetal cortical development and glutamatergic neurons are affected by mutations in ASD, suggesting it is a robust finding.
“Other studies have also found that fetal cortical development and glutamatergic neurons are affected by mutations in ASD, suggesting that it is a robust finding11,113,114.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [114]
FMRP targets are connected to multiple forms of ASD genetic risk, including copy number variations, by genome-wide and seeded co-expression network analyses.
“Both genome-wide27 and seeded114 co-expression network analysis further connected FMRP targets with multiple forms of ASD genetic risk, including copy number variations (CNVs)114.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [114]
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- Authors
- Steinberg, J., & Webber, C.
- Affiliations
- Centre for Human Genetics (GB)
- University of Oxford (GB)
- Corresponding author
- Webber, Caleb
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 93
- Issue
- 5
- Pages
- 825-839
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3824119
- OpenAlex
- W2129279571
- Cited by
- 71
- References
- 58
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 4 · 2022: 1 · 2021: 7 · 2020: 1 · 2019: 12 · 2018: 5 · 2017: 10 · 2016: 6 · 2015: 12 · 2014: 6
- FWCI
- 5.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Funders
- Autism Speaks
- Wellcome Trust (090532/Z/09/Z, 093941/Z/10/Z)
- European Commission
- National Institutes of Health
- National Institute of Mental Health (U24MH081810)
- 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 › Genetics › Genomics and Rare Diseases
- Keywords
- autism spectrum disorder, FMRP, trend tests, ultra-rare variants, copy number variation, neuroplasticity, synaptic genes, de novo mutations
- MeSH terms
- Brain, Child Development Disorders, Pervasive, Humans, Mutation, Up-Regulation, Sequence Analysis, RNA, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein, Genetic Association Studies, DNA Copy Number Variations, Exome
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