Multidisciplinary approach to identify gene-environment interplay triggering autism
-
1
Institute of Biomedical Technologies, National Research Council, Italy
-
2
IRCSS Eugenio Medea, Italy
-
3
University of Salerno, Department of Chemistry and Biology, Italy
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and interaction, restricted interests and repetitive behaviours. Many ASD patients suffer of comorbidities including epilepsy, sleep problems, metabolic conditions and gastrointestinal disorders (GID) [1].
Although causative mutations have been found in ~30% of autistic children, for most of the patients the cause of the disease is still unclear. Recent findings suggest that gene-environment interaction plays an important role in the aetiology of the disorder.
Among environmental factors, gut microbiota are now receiving great attention as possible triggering agent of autism. Metagenomics analyses of gut microbioma of ASD children with GID and intestinal permeability have found dysbiosis [2] that correlates with disease risk and severity probably through a microbiota-gut-brain axis [3,4]. Indeed, intestinal pathogens lead to impairment of immune system, to production of toxins and neurochemical compounds and to leaky gut causing the adsorption of many xenobiotics [5]. In addition to gut pathogens, a genetic predisposition and an alimentary factor increasing intestinal permeability were also found. The genetic risk was imputed to haptoglobin gene (HP), that plays a key role in the regulation of intestinal tight junction. This gene has 2 common co-dominant alleles whose distribution is different between several immune-mediated diseases, including schizophrenia, and healthy population [6]. The alimentary cause is imputed to gliadin (a component of gluten), that binds to the chemokine receptor CXCR3 that, in turn, activates haptoglobin [7] thus enhancing gut permeability.
On the other hand, circulating microRNAs are a promising class of biomarkers for many diseases, including autism [8], and for their prognosis definition. Recently, among circulating human microRNAs, exogenous RNAs (xenomiRs) from plants (diet-derived), bacteria and fungi were found as part of a circulating RNA homeostasis [9,10].
In this scenario, we have recruited 222 ASD patients and 100 controls and collected biological samples and clinical data as well as the alimentary diary. We are performing a multidisciplinary analysis in order to identify the genetic risk factor(s) and the environmental cause(s) triggering the disease.
To this purpose high-density genotyping analysis, by “HumanOmni1S-8 v1.0 DNA Analysis BeadChip”, has been carried out on both patients and controls and bioinformatics GWAs is in progress. HP genotype will be also analyzed in the same samples.
Parallel, circulating total RNAs have been isolated from the serum of a subgroup of 25 ASD patients and 25 controls and the quantification of a set of human microRNA is nearing completion.
In serum samples food intolerances have been analyzed too.
Neuroinformatics integration of the obtained results with the available gene list of corresponding anatomical structure(s) and with data available from Allen Human Brain Atlas [11,12] will be performed in the frame of the INCF Digital Atlasing Program
Further ASD patients suffering from GID and healthy controls will be recruited and samples of blood, serum and feces collected as well as clinical data and dietary diary. GWAs, circulating RNAseq and stool metagenomics analyses will be performed on biological samples in order to identify the endogenous (genetic risk and human circulating microRNAs) and exogenous (microbiota and xenomiRs) profile of ASD patients and controls. All the data obtained will be submitted to a neuroinformatics integration and systems biology analysis to find a possible gene-environmental cross-talk via epigenetic mechanisms.
Acknowledgements
ACKNOWLEDGEMENTS: Italian Ministry of Education and Research: Flagship project InterOmics (PB05); Italian Ministry of Health: GR-2009-1570296; FP7 "Mimomics” European project.
References
1 Coury DL, Ashwood P, Fasano A, Fuchs G, Geraghty M, Kaul A et al. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics (2012) 130(2):S160-8. doi: 10.1542/peds.2012-0900N.
2 Williams BL, Hornig M, Buie T, Bauman ML, Cho Paik M, Wick I et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS One (2011) 6(9):e24585. doi: 10.1371/journal.pone.0024585.
3 EY. Hsiao. Gastrointestinal Issues in Autism Spectrum Disorder. www.harvardreviewofpsychiatry.org (2014) 22(2)
4 Rosenfeld CS. Microbiome Disturbances and Autism Spectrum Disorders. Drug Metab Dispos (2015) 7. pii: dmd.115.063826.
5 Mezzelani A, Landini M, Facchiano F, Raggi ME, Villa L, Molteni M et al. Environment, dysbiosis, immunity and sex-specific susceptibility: A translational hypothesis for regressive autism pathogenesis. Nutr Neurosci (2015) 18(4):145-61. doi: 10.1179/1476830513Y.0000000108
6 Fasano A Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. (2012) 1258:25-33. doi: 10.1111/j.1749-6632.2012.06538.x.
7 Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology (2008) 135(1):194-204.e3. doi: 10.1053/j.gastro.2008.03.023.
8 Mundalil Vasu M, Anitha A, Thanseem I, Suzuki K, Yamada K, Takahashi T et al. Serum microRNA profiles in children with autism. Mol Autism (2014) 30;5:40. doi: 10.1186/2040-2392-5-40
9 Witwer KW. XenomiRs and miRNA homeostasis in health and disease: evidence that diet and dietary miRNAs directly and indirectly influence circulating miRNA profiles. RNA Biol. (2012) 9(9):1147-54. doi: 10.4161/rna.21619
10 Beatty M, Guduric-Fuchs J, Brown E, Bridgett S, Chakravarthy U, Hogg RE et al. Small RNAs from plants, bacteria and fungi within the order Hypocreales are ubiquitous in human plasma. BMC Genomics (2014) 25;15:933. doi: 10.1186/1471-2164-15-933.
11 Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA et al. An anatomically comprehensive atlas of the adult human brain transcriptome. (2012) Nature 489: 391-399. doi: 10.1038/nature11405
12 Website: ©2014 Allen Institute for Brain Science. Allen Human Brain Atlas [Internet]. Available from: http://human.brain-map.org/
Keywords:
Autism spectrum disorders (ASD),
gene environment interactions,
genotyping,
Circulating microRNA,
xenomiRs,
Metagenomics,
epigenetics,
microbiota–gut–brain axis,
Bioinformatics & Computational Biology,
Systems Biology
Conference:
Neuroinformatics 2015, Cairns, Australia, 20 Aug - 22 Aug, 2015.
Presentation Type:
Poster, not to be considered for oral presentation
Topic:
General neuroinformatics
Citation:
Mezzelani
A,
Gnocchi
M,
Mosca
E,
Raggi
ME,
Marabotti
A and
Milanesi
L
(2015). Multidisciplinary approach to identify gene-environment interplay triggering autism.
Front. Neurosci.
Conference Abstract:
Neuroinformatics 2015.
doi: 10.3389/conf.fnins.2015.91.00045
Copyright:
The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers.
They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.
The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.
Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.
For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.
Received:
03 May 2015;
Published Online:
05 Aug 2015.
*
Correspondence:
Dr. Alessandra Mezzelani, Institute of Biomedical Technologies, National Research Council, Segrate (MI), 20090, Italy, alessandra.mezzelani@itb.cnr.it
Dr. Luciano Milanesi, Institute of Biomedical Technologies, National Research Council, Segrate (MI), 20090, Italy, luciano.milanesi@itb.cnr.it