title: Predicting the diagnosis of autism spectrum disorder using gene pathway analysis.
abstract: Autism spectrum disorder (ASD) depends on a clinical interview with no biomarkers to aid diagnosis. The current investigation interrogated single-nucleotide polymorphisms (SNPs) of individuals with ASD from the Autism Genetic Resource Exchange (AGRE) database. SNPs were mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived pathways to identify affected cellular processes and develop a diagnostic test. This test was then applied to two independent samples from the Simons Foundation Autism Research Initiative (SFARI) and Wellcome Trust 1958 normal birth cohort (WTBC) for validation. Using AGRE SNP data from a Central European (CEU) cohort, we created a genetic diagnostic classifier consisting of 237 SNPs in 146 genes that correctly predicted ASD diagnosis in 85.6% of CEU cases. This classifier also predicted 84.3% of cases in an ethnically related Tuscan cohort; however, prediction was less accurate (56.4%) in a genetically dissimilar Han Chinese cohort (HAN). Eight SNPs in three genes (KCNMB4, GNAO1, GRM5) had the largest effect in the classifier with some acting as vulnerability SNPs, whereas others were protective. Prediction accuracy diminished as the number of SNPs analyzed in the model was decreased. Our diagnostic classifier correctly predicted ASD diagnosis with an accuracy of 71.7% in CEU individuals from the SFARI (ASD) and WTBC (controls) validation data sets. In conclusion, we have developed an accurate diagnostic test for a genetically homogeneous group to aid in early detection of ASD. While SNPs differ across ethnic groups, our pathway approach identified cellular processes common to ASD across ethnicities. Our results have wide implications for detection, intervention and prevention of ASD.
authors.affiliation: Centre for Neural Engineering, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Skafidas
authors.affiliation: 1] Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Parkville, VIC, Australia [2] Department of Psychology, Monash University, Clayton, VIC, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Testa
authors.affiliation: Department of Haematology, Austin Health, Heidelberg, VIC, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Zantomio
authors.affiliation: Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Chana
authors.affiliation: Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: I P
authors.initials: IP
authors.lastname: Everall
authors.affiliation: 1] Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Parkville, VIC, Australia [2] Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Pantelis
mesh_terms: D044466:Asian People / Q000208:ethnology / Q000235:genetics; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis* / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C584143:GNAO1 protein, human; C578935:GRM5 protein, human; C410183:KCNMB4 protein, human; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D009419:Nerve Tissue Proteins; D064529:Receptor, Metabotropic Glutamate 5; D019206:GTP-Binding Protein alpha Subunits, Gi-Go