Distinct Genetic Risk Based on Association of MET in Families With Co-occurring Autism and Gastrointestinal Conditions
Abstract
OBJECTIVE. In addition to the core behavioral symptoms of autism spectrum disorder, many patients present with complex medical conditions including gastrointestinal dysfunction. A functional variant in the promoter of the gene encoding the MET receptor tyrosine kinase is associated with autism spectrum disorder, and MET protein expression is decreased in the temporal cortex of subjects with autism spectrum disorder. MET is a pleiotropic receptor that functions in both brain development and gastrointestinal repair. On the basis of these functions, we hypothesized that association of the autism spectrum disorder–associated MET promoter variant may be enriched in a subset of individuals with co-occurring autism spectrum disorder and gastrointestinal conditions. PATIENTS AND METHODS. Subjects were 918 individuals from 214 Autism Genetics Resource Exchange families with a complete medical history including gastrointestinal condition report. Genotypes at the autism spectrum disorder–associated MET promoter variant rs1858830 were determined. Family-based association test and χ2 analyses were used to determine the association of MET rs1858830 alleles with autism spectrum disorder and the presence of gastrointestinal conditions. RESULTS. In the entire 214-family sample, the MET rs1858830 C allele was associated with both autism spectrum disorder and gastrointestinal conditions. Stratification by the presence of gastrointestinal conditions revealed that the MET C allele was associated with both autism spectrum disorder and gastrointestinal conditions in 118 families containing at least 1 child with co-occurring autism spectrum disorder and gastrointestinal conditions. In contrast, there was no association of the MET polymorphism with autism spectrum disorder in the 96 families lacking a child with co-occurring autism spectrum disorder and gastrointestinal conditions. χ2 analyses of MET rs1858830 genotypes indicated over-representation of the C allele in individuals with co-occurring autism spectrum disorder and gastrointestinal conditions compared with non-autism spectrum disorder siblings, parents, and unrelated controls. CONCLUSION. These results suggest that disrupted MET signaling may contribute to increased risk for autism spectrum disorder that includes familial gastrointestinal dysfunction.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Children with ASD and MET gene mutations were more likely to have gastrointestinal disorders.
“Campbell et al 66 reported that children with ASD and MET gene mutations were more likely to have gastrointestinal disorders, raising the possibility that medical comorbidities in children with ASD could index underlying genetic heterogeneity.”
From Early Intervention for Children With Autism Spectrum Disorder Under 3 Years of Age: Recommendations for Practice and Research (2015) · cites this paper as [66]
A polymorphism of the MET tyrosine receptor kinase is associated with both ASD and GI dysfunction in family samples.
“For example, a polymorphism of the MET tyrosine receptor kinase is associated with both ASD and GI dysfunction in family samples, elucidating a potential genetic connection of the two pathologies 41.”
From Gastrointestinal Issues and Autism Spectrum Disorder (2020) · cites this paper as [41]
Children with ASD and GI pain may present with non-specific signs or symptoms including aggression, self-injury, irritability, abnormal vocalizations, motor signs, hyperactivity, changes in sleep patterns and/or anxiety.
“Consequently, children with ASD and GI pain may present with non-specific signs or symptoms to express their discomfort, including aggression, self-injury, irritability, abnormal vocalizations (i.e. frequent swallowing, moaning), motor signs (i.e. grimacing, tapping), hyperactivity, changes in sleep patterns and/or anxiety 7325414.”
From Gastrointestinal Issues and Autism Spectrum Disorder (2020) · cites this paper as [41]
Cites
Neuroglial activation and neuroinflammation in the brain of patients with autism
Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W., & Pardo, C. A. (2005) · Annals of Neurology · doi:10.1002/ana.20315 · Cited by 2,149 · see citing works
Autism spectrum disorders: developmental disconnection syndromes
Geschwind, D. H., & Levitt, P. (2007) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2007.01.009 · Cited by 1,411 · see citing works
Self-citationSearching for ways out of the autism maze: genetic, epigenetic and environmental clues
Persico, A. M., & Bourgeron, T. (2006) · Trends in Neurosciences · doi:10.1016/j.tins.2006.05.010 · Cited by 575 · see citing works
Gastrointestinal abnormalities in children with autistic disorder
Horváth, K., Papadimitriou, J. C., Rabsztyn, A., Drachenberg, C. B., & Tildón, J. T. (1999) · The Journal of Pediatrics · doi:10.1016/s0022-3476(99)70052-1 · Cited by 489 · see citing works
Immunity, neuroglia and neuroinflammation in autism
Pardo, C. A., Vargas, D. L., & Zimmerman, A. W. (2005) · International Review of Psychiatry · doi:10.1080/02646830500381930 · Cited by 460 · see citing works
A genetic variant that disrupts <i>MET</i> transcription is associated with autism
Campbell, D. B., Sutcliffe, J. S., Ebert, P. J., Militerni, R., Bravaccio, C., Trillo, S., Elia, M., Schneider, C., Melmed, R., Sacco, R., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605296103 · Cited by 401 · see citing works
Self-citationPowell, E. M., Campbell, D. B., Stanwood, G. D., Davis, C., Noebels, J. L., & Levitt, P. R. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-02-00622.2003 · Cited by 333 · see citing works
Self-citationPowell, E. M., Mars, W. M., & Levitt, P. (2001) · Neuron · doi:10.1016/s0896-6273(01)00264-1 · Cited by 321 · see citing works
Self-citationVALICENTI-McDERMOTT, M., McVICAR, K., RAPIN, I., WERSHIL, B. K., COHEN, H., & SHINNAR, S. (2006) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/00004703-200604002-00011 · Cited by 302 · see citing works
Molloy, C. A., & Manning-Courtney, P. (2003) · Autism · doi:10.1177/1362361303007002004 · Cited by 249 · see citing works
Okunishi, K., Dohi, M., Nakagome, K., Tanaka, R., Mizuno, S., Matsumoto, K., Miyazaki, J., Nakamura, T., & Yamamoto, K. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.7.4745 · Cited by 244 · see citing works
Black, C., Kaye, J. A., & Jick, H. (2002) · BMJ · doi:10.1136/bmj.325.7361.419 · Cited by 240 · see citing works
Recent Advances in the Genetics of Autism
Gupta, A. R., & State, M. W. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.06.020 · Cited by 203 · see citing works
Disruption of cerebral cortex MET signaling in autism spectrum disorder
Campbell, D. B., D'Oronzio, R., Garbett, K., Ebert, P. J., Mirnics, K., Levitt, P., & Persico, A. M. (2007) · Annals of Neurology · doi:10.1002/ana.21180 · Cited by 193 · see citing works
Self-citationGastrointestinal Factors in Autistic Disorder: A Critical Review
Erickson, C. A., Stigler, K. A., Corkins, M. R., Posey, D. J., Fitzgerald, J. F., & McDougle, C. J. (2005) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-005-0019-4 · Cited by 165 · see citing works
Levy, S. E., Souders, M. C., Ittenbach, R. F., Giarelli, E., Mulberg, A. E., & Pinto-Martin, J. A. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.07.013 · Cited by 130 · see citing works
Disruption of Interneuron Development
Levitt, P. R. (2005) · Epilepsia · doi:10.1111/j.1528-1167.2005.00305.x · Cited by 128 · see citing works
Self-citationYang, M. S., & Gill, M. (2006) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2006.12.002 · Cited by 118 · see citing works
Tahara, Y., Ido, A., Yamamoto, S., Miyata, Y., Uto, H., Hori, T., Hayashi, K., & Tsubouchi, H. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.054106 · Cited by 102 · see citing works
HGF regulates the development of cortical pyramidal dendrites
Gutiérrez, H., Dolcet, X., Tolcos, M., & Davies, A. (2004) · Development · doi:10.1242/dev.01209 · Cited by 91 · see citing works
Ieraci, A., Forni, P. E., & Ponzetto, C. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.222362099 · Cited by 89 · see citing works
Hepatocyte growth factor–stimulated invasiveness of monocytes
Beilmann, M., Woude, G. F. V., Dienes, H., & Schirmacher, P. (2000) · Blood · doi:10.1182/blood.v95.12.3964 · Cited by 79 · see citing works
Beilmann, M., Odenthal, M., Jung, W., Woude, G. F. V., Dienes, H., & Schirmacher, P. (1997) · Blood · doi:10.1182/blood.v90.11.4450 · Cited by 75 · see citing works
Hepatocyte growth factor as an enhancer of nmda currents and synaptic plasticity in the hippocampus
Akimoto, M., Baba, A., Ikeda-Matsuo, Y., Yamada, M. K., Itamura, R., Nishiyama, N., Ikegaya, Y., & Matsuki, N. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.06.031 · Cited by 71 · see citing works
Ido, A., Numata, M., Kodama, M., & Tsubouchi, H. (2005) · Journal of Gastroenterology · doi:10.1007/s00535-005-1705-x · Cited by 70 · see citing works
Tyndall, S. J., & Walikonis, R. S. (2006) · Cell Cycle · doi:10.4161/cc.5.14.2918 · Cited by 58 · see citing works
Eagleson, K. L., Bonnin, A., & Levitt, P. R. (2005) · The Journal of Comparative Neurology · doi:10.1002/cne.20647 · Cited by 53 · see citing works
Self-citationArthur, L. G., Schwartz, M. Z., Kuenzler, K. A., & Birbe, R. (2004) · Journal of Pediatric Surgery · doi:10.1016/j.jpedsurg.2003.10.001 · Cited by 35 · see citing works
Autism and the gastrointestinal tract
Quigley, E. M. M., & Hurley, D. (2000) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2000.03247.x · Cited by 29 · see citing works
Tyndall, S. J., & Walikonis, R. S. (2007) · Synapse · doi:10.1002/syn.20362 · Cited by 29 · see citing works
Attenuation of mouse acute colitis by naked hepatocyte growth factor gene transfer into the liver
Hanawa, T., Suzuki, K., Kawauchi, Y., Takamura, M., Yoneyama, H., Han, G., Kawachi, H., Shimizu, F., Asakura, H., Miyazaki, J., et al. (2006) · Journal of Gene Medicine · doi:10.1002/jgm.880 · Cited by 25 · see citing works
Hepatocyte growth factor ameliorates inflammatory bowel disease in a rat model
Arthur, L. G., Kuenzler, K. A., & Schwartz, M. Z. (2003) · Journal of Gastrointestinal Surgery · doi:10.1016/j.gassur.2003.09.014 · Cited by 14 · see citing works
Beilmann, M., Odenthal, M., Jung, W., et al. (1997) · Blood · doi:10.1182/blood.v90.11.4450.4450_4450_4458 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Buie, T., Campbell, D. B., Fuchs, G. J., Furuta, G. T., Levy, J., VandeWater, J., Whitaker, A. H., Atkins, D., Bauman, M. L., Beaudet, A. L., et al. (2010) · Pediatrics · doi:10.1542/peds.2009-1878c · Cited by 872 · see citing works
Self-citationMaternal infection and immune involvement in autism
Patterson, P. H. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2011.03.001 · Cited by 520 · see citing works
Altered gut microbiota and short chain fatty acids in Chinese children with autism spectrum disorder
Liu, S., Li, E., Sun, Z., Fu, D., Duan, G., Jiang, M., Yu, Y., Mei, L., Yang, P., Tang, Y., et al. (2019) · Scientific Reports · doi:10.1038/s41598-018-36430-z · Cited by 457 · see citing works
Wang, L., Christophersen, C. T., Sorich, M. J., Gerber, J. P., Angley, M. T., & Conlon, M. A. (2012) · Digestive Diseases and Sciences · doi:10.1007/s10620-012-2167-7 · Cited by 412 · see citing works
Medical Comorbidities in Autism: Challenges to Diagnosis and Treatment
Bauman, M. L. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.06.001 · Cited by 372 · see citing works
Self-citationGastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors
Gorrindo, P., Williams, K. C., Lee, E. B., Walker, L. S., McGrew, S. G., & Levitt, P. (2012) · Autism Research · doi:10.1002/aur.237 · Cited by 325 · see citing works
Self-citationThe conundrums of understanding genetic risks for autism spectrum disorders
State, M. W., & Levitt, P. (2011) · Nature Neuroscience · doi:10.1038/nn.2924 · Cited by 306 · see citing works
Self-citationThe bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior
Arentsen, T., Qian, Y., Gkotzis, S., Femenia, T., Wang, T., Udekwu, K., Forssberg, H., & Diaz Heijtz, R. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.182 · Cited by 280 · see citing works
Wang, L. W., Tancredi, D. J., & Thomas, D. W. (2011) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/dbp.0b013e31821bd06a · Cited by 258 · see citing works
Gastrointestinal issues in autism spectrum disorder
Hsiao, E. Y. (2014) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000029 · Cited by 209 · see citing works
Use of psychotropic medication in children and adolescents with autism spectrum disorders
Coury, D. L., Anagnostou, E., Manning-Courtney, P., Reynolds, A., Cole, L., McCoy, R., Whitaker, A., & Perrin, J. M. (2012) · PEDIATRICS · doi:10.1542/peds.2012-0900d · Cited by 191 · see citing works
Self-citationTye, C., Runicles, A. K., Whitehouse, A. J. O., & Alvares, G. A. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00751 · Cited by 177 · see citing works
Gastrointestinal Issues and Autism Spectrum Disorder
Madra, M., Ringel, R., & Margolis, K. G. (2020) · Child and Adolescent Psychiatric Clinics of North America · doi:10.1016/j.chc.2020.02.005 · Cited by 159 · see citing works
The Impact of Neuroimmune Alterations in Autism Spectrum Disorder
Gottfried, C., Bambini-Junior, V., Francis, F., Riesgo, R., & Savino, W. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2015.00121 · Cited by 143 · see citing works
Bresnahan, M., Hornig, M., Schultz, A. F., Gunnes, N., Hirtz, D., Lie, K. K., Magnus, P., Reichborn-Kjennerud, T., Roth, C., Schjølberg, S., et al. (2015) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2014.3034 · Cited by 132 · see citing works
Aldinger, K. A., Lane, C. J., Veenstra‐VanderWeele, J., & Levitt, P. (2015) · Autism Research · doi:10.1002/aur.1492 · Cited by 125 · see citing works
Self-citationVeenstra-VanderWeele, J., & Blakely, R. D. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.185 · Cited by 128 · see citing works
Lefter, R., Ciobica, A., Timofte, D., Stanciu, C., & Trifan, A. (2019) · Medicina · doi:10.3390/medicina56010011 · Cited by 120 · see citing works
Detection of Clostridium perfringens toxin genes in the gut microbiota of autistic children
Finegold, S. M., Summanen, P. H., Downes, J., Corbett, K., & Komoriya, T. (2017) · Anaerobe · doi:10.1016/j.anaerobe.2017.02.008 · Cited by 110 · see citing works
Qiu, S., Anderson, C. T., Levitt, P., & Shepherd, G. M. G. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6569-10.2011 · Cited by 106 · see citing works
Self-citationThe relationship of autism and gluten
Buie, T. (2013) · Clinical Therapeutics · doi:10.1016/j.clinthera.2013.04.011 · Cited by 91 · see citing works
Self-citationRigid-compulsive behaviors are associated with mixed bowel symptoms in autism spectrum disorder
Peters, B., Williams, K. C., Gorrindo, P., Rosenberg, D., Lee, E. B., Levitt, P., & Veenstra-VanderWeele, J. (2014) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-013-2009-2 · Cited by 70 · see citing works
Self-citationSheng, L., Ding, X., Ferguson, M., McCallister, M., Rhoades, R., Maguire, M., Ramesh, A., Aschner, M., Campbell, D., Levitt, P., et al. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq304 · Cited by 63 · see citing works
Self-citationHeuer, L., Braunschweig, D., Ashwood, P., Van de Water, J., & Campbell, D. B. (2011) · Translational Psychiatry · doi:10.1038/tp.2011.48 · Cited by 62 · see citing works
Self-citationMET Receptor Tyrosine Kinase as an Autism Genetic Risk Factor
Peng, Y., Huentelman, M., Smith, C., & Qiu, S. (2013) · International Review of Neurobiology · doi:10.1016/b978-0-12-418700-9.00005-8 · Cited by 49 · see citing works
A new synaptic player leading to autism risk: Met receptor tyrosine kinase
Judson, M. C., Eagleson, K. L., & Levitt, P. (2011) · Journal of Neurodevelopmental Disorders · doi:10.1007/s11689-011-9081-8 · Cited by 43 · see citing works
Self-citationIsaksson, J., Pettersson, E., Kostrzewa, E., Diaz Heijtz, R., & Bölte, S. (2017) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-017-3169-2 · Cited by 31 · see citing works
- Authors
- Campbell, D. B., Buie, T. M., Winter, H., Bauman, M., Sutcliffe, J. S., Perrin, J. M., & Levitt, P.
- Affiliations
- Vanderbilt University (US)
- Harvard University (US)
- Venue
- Pediatrics
- Publisher
- American Academy of Pediatrics (AAP)
- Published
- 2009-03-01
- Volume
- 123
- Issue
- 3
- Pages
- 1018-1024
- ISSN
- 0031-4005 (ISSN-L)
- 1098-4275
- OpenAlex
- W2106428414
- Cited by
- 145
- References
- 33
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2023: 4 · 2022: 2 · 2021: 7 · 2020: 6 · 2019: 9 · 2018: 4 · 2017: 10 · 2016: 10 · 2015: 7 · 2014: 9 · 2013: 14 · 2012: 11
- FWCI
- 8.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- PEDIATRICS (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH065299)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD015052, HD015052)
- 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 › Genetic Associations and Epidemiology
- Keywords
- autism spectrum disorder, gastrointestinal dysfunction, MET receptor tyrosine kinase, genetic risk, familial aggregation, family-based association
- MeSH terms
- Alleles, Autistic Disorder, Child, Female, Gastrointestinal Diseases, Genotype, Humans, Male, Phenotype, Promoter Regions, Genetic, Proto-Oncogene Proteins, Risk Factors, Signal Transduction, Linkage Disequilibrium, Comorbidity, Receptors, Growth Factor, Proto-Oncogene Proteins c-met, Genetic Predisposition to Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
