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Title: Predicting the diagnosis of autism spectrum disorder using gene pathway analysis.
Austin Authors: Skafidas, E;Testa, R;Zantomio, D ;Chana, Gursharan;Everall, I P;Pantelis, C
Affiliation: Centre for Neural Engineering, The University of Melbourne, Parkville, Victoria, Australia
Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia
Department of Haematology, Austin Health, Heidelberg, Victoria, Australia
Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Parkville, VIC, Australia
Department of Psychology, Monash University, Clayton, VIC, Australia
Issue Date: 11-Sep-2012
Publication information: Molecular Psychiatry 2012; 19(4): 504-10
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.
Gov't Doc #: 22965006
DOI: 10.1038/mp.2012.126
Type: Journal Article
Subjects: Asian Continental Ancestry Group.ethnology.genetics
Child Development Disorders, Pervasive.diagnosis.genetics
Cohort Studies
European Continental Ancestry Group.genetics
GTP-Binding Protein alpha Subunits, Gi-Go.genetics
Gene Regulatory Networks.genetics
Genetic Predisposition to Disease.genetics
Genetic Testing
Large-Conductance Calcium-Activated Potassium Channel beta Subunits.genetics
Nerve Tissue Proteins.genetics
Polymorphism, Single Nucleotide.genetics
Receptor, Metabotropic Glutamate 5.genetics
Appears in Collections:Journal articles

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