Identifying autism loci and genes by tracing recent shared ancestry
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To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 ( protocadherin 10 ) and DIA1 ( deleted in autism1 , or c3orf58) , whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 ( Na + /H + exchanger 9 ), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of âhomozygosity mappingâ in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.
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The broader protein family that includes CDH13 has been linked to ASD pathogenesis by CNV studies, homozygosity mapping, common variant findings, and the paper's pathway analysis.
“the larger family of proteins has been implicated in ASD pathogenesis through CNV studies (Glessner et al., 2009), homozygosity mapping (Morrow et al., 2008), common variant findings (Wang et al., 2009), and our pathway analysis (Figure 6)”
From Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism (2011) · cites this paper as Morrow et al., 2008
Only 3% of the transcriptome is expressed in an activity-dependent manner, but a much larger fraction of ASD-implicated genes show activity-dependent expression.
“The idea that defects in activity-induced gene expression contribute to ASD was initially based on a provocative realization: while only 3% of the transcriptome is expressed in an activity-dependent manner, a far greater percentage of ASD implicated genes display activity-dependent expression (Kelleher and Bear, 2008; Morrow et al., 2008).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Morrow et al., 2008
Studies have implicated homozygous copy number variants and long homozygous intervals as significantly associated with ASDs.
“Additional evidence supporting a role of biallelic mutations comes from studies that have implicated homozygous CNVs (Levy et al., 2011; Morrow et al., 2008) and long homozygous intervals as significantly associated with ASDs (Casey et al., 2012).”
From Using Whole-Exome Sequencing to Identify Inherited Causes of Autism (2013) · cites this paper as Morrow et al., 2008
The data demonstrate that biallelic hypomorphic mutations underlie at least a subset of ASDs.
“Our data combine WES with segregation analysis to demonstrate that biallelic, hypomorphic mutations underlie at least a subset of ASDs (Chahrour et al., 2012; Morrow et al., 2008).”
From Using Whole-Exome Sequencing to Identify Inherited Causes of Autism (2013) · cites this paper as Morrow et al., 2008
Only about 3% of the neuronal transcriptome is altered by membrane depolarization, but a higher percentage of ASD-implicated genes are regulated by neuronal activity.
“Only about 3% of the neuronal transcriptome is altered when the membrane is depolarized, but a higher percentage of the genes that are implicated in ASD have been shown to be regulated by neuronal activity, it has been proposed, therefore, that ASD may result, at least in part, from the disruption of the activity-dependent signalling networks that control gene transcription34,35.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [34]
Knockdown of transcription factors mediating activity-regulated gene transcription, including MEF2 and NPAS4, decreased expression of multiple ASD-linked genes (c3orf58, SLC9A9, PCDH10).
“In addition, knockdown of several transcription factors that mediate activity-regulated gene transcription, including MEF2 and NPAS4, led to decreased expression of multiple genes that are linked to ASD (c3orf58, SLC9A9, and PCDH10)34.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [34]
Several genetic loci associated with ASD (UBE3B, CLTCL1, NCKAP5L, ZNF18) include genes whose expression is induced by neuronal activity.
“Several genetic loci (UBE3B, CLTCL1, NCKAP5L and ZNF18) that are associated with ASD include genes for which expression is induced by neuronal activity34,35.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [34]
It has been proposed that ASD may result, at least in part, from disruption of activity-dependent signalling networks that control gene transcription.
“Only about 3% of the neuronal transcriptome is altered when the membrane is depolarized, but a higher percentage of the genes that are implicated in ASD have been shown to be regulated by neuronal activity, it has been proposed, therefore, that ASD may result, at least in part, from the disruption of the activity-dependent signalling networks that control gene transcription34,35.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [34]
Reference 34 provides evidence that genetic mutations linked to autism may disrupt activity-dependent gene expression programs.
“This paper provides evidence for the hypothesis that genetic mutations associated with autism may disrupt activity-dependent gene expression programs.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [34]
DNA sequencing in consanguineous families is an effective approach for identifying ASD attributable to rare homozygous variants.
“DNA sequencing in such families is an effective approach for identifying cases of ASD that are attributable to rare homozygous variants (Morrow et al., 2008; Scott et al., 2016).”
From Getting to the cores of autism (2019) · cites this paper as Morrow et al., 2008
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- Authors
- Morrow, E. M., Yoo, S.-Y., Flavell, S. W., Kim, T.-K., Lin, Y., Hill, R. S., Mukaddes, N. M., Balkhy, S., Gascon, G., Hashmi, A., Al-Saad, S., Ware, J., Joseph, R. M., Greenblatt, R., Gleason, D., Ertelt, J. A., Apse, K. A., Bodell, A., Partlow, J. N., Barry, B., Yao, H., Markianos, K., Ferland, R. J., Greenberg, M. E., & Walsh, C. A.
- Affiliations
- Broad Institute (US)
- ORCID
- Venue
- Science
- Published
- 2008-07-11
- Volume
- 321
- Issue
- 5886
- Pages
- 218-223
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2586171
- OpenAlex
- W2158778721
- Cited by
- 737
- References
- 44
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 12 · 2023: 11 · 2022: 24 · 2021: 26 · 2020: 39 · 2019: 25 · 2018: 30 · 2017: 37 · 2016: 43 · 2015: 34 · 2014: 47 · 2013: 74 · 2012: 55
- FWCI
- 44.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Open Access System for Information Sharing (Pohang University of Science and Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (n01hg065403-000, 5r01ns048276-15)
- National Institute of Mental Health (R01MH083565, K01MH071801, K23MH080954, MH 64547, 1K01MH71801, R01MH064547)
- National Human Genome Research Institute (N01 HG-65403)
- National Institute of Neurological Disorders and Stroke (5R01NS048276-05, R01-NS-048276)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- autism spectrum disorder, homozygosity mapping, shared ancestry, homozygous deletion, PCDH10, Dia1, NHE9, inherited mutations, synaptic gene expression, neuronal activity, gene expression regulation, genetic loci
- MeSH terms
- Formins, Protocadherins, Animals, Autistic Disorder, Brain, Chromosome Mapping, Consanguinity, Female, Gene Expression Regulation, Genes, Recessive, Homozygote, Humans, Lod Score, Male, Mutation, Neurons, Pedigree, Transcription Factors, Cadherins, Gene Deletion, Sodium-Hydrogen Exchangers, Gene Dosage, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Adaptor Proteins, Signal Transducing, Rats
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