Genome, Environment, Microbiome and Metabolome in Autism (GEMMA) study design: Biomarkers identification for precision treatment and primary prevention of Autism Spectrum Disorders by an integrated multi-omics systems biology approach

Autism Spectrum Disorder (ASD) affects approximately 1 child in 54, with a 35-fold increase since 1960. Selected studies suggest that part of the recent increase in prevalence is likely attributable to an improved awareness and recognition, and changes in clinical practice or service availability. However, this is not sufficient to explain this epidemiological phenomenon. Research points to a possible link between ASD and intestinal microbiota because many children with ASD display gastro-intestinal problems. Current large-scale datasets of ASD are limited in their ability to provide mechanistic insight into ASD because they are predominantly cross-sectional studies that do not allow evaluation of perspective associations between early life microbiota composition/function and later ASD diagnoses. Here we describe GEMMA (Genome, Environment, Microbiome and Metabolome in Autism), a prospective study supported by the European Commission, that follows at-risk infants from birth to identify potential biomarker predictors of ASD development followed by validation on large multi-omics datasets. The project includes clinical (observational and interventional trials) and pre-clinical studies in humanized murine models (fecal transfer from ASD probands) and in vitro colon models. This will support the progress of a microbiome-wide association study (of human participants) to identify prognostic microbiome signatures and metabolic pathways underlying mechanisms for ASD progression and severity and potential treatment response.This work is conducted with support from the Advisory Board Members (California Institute of Technology, Winclove Probiotics, University of California Davis, Center for Autism and the Developing Brain, Ohio State University, the Autism Speaks Autism Treatment Network, Arizona State University, University College Cork), from the Consortium Partners: Fondazione EBRIS, in charge of project management and coordination and providing the gut permeability and immunological evaluation of the enrolled subjects; Nutricia Research Bv in charge of nutritional formulation development for interventional trial; Medinok Spa and Consiglio Nazionale Delle Ricerche (CNR) in charge of data analysis and multi-omics platform development; Bio Modeling Systems in charge of the mechanistic pathway hypothesis development; Euformatics in charge of analysis and the interpretation of the genomic variants of the patient material, and for the comparison of the variants from the different patient cohorts, Theoreo Srl and Imperial College Of Science in charge of metabolomics analysis and interpretation; National University of Ireland Galway, Azienda Sanitaria, Locale (ASL) Salerno and Massachusettse General Hospital for Children, in charge of enrollments for observation and interventional trials; Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement in charge of analyzing the genomic and transcriptomic profiles of the host microbiota; Institut National de la Santé et de la Recherche Médicale, in charge of proteomics analysis; Utrecht University, in charge of pre-clinical studies; Tampereen Yliopisto, in charge of experimental design; Johns Hopkins University in charge of epigenomic evaluation and interpretation. Financial contributions were made by European Union.peer-reviewe