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Open Access Research article

Pathway-based outlier method reveals heterogeneous genomic structure of autism in blood transcriptome

Malcolm G Campbell123, Isaac S Kohane12 and Sek Won Kong12*

Author Affiliations

1 Center for Biomedical Informatics, Harvard Medical School, 10 Shattuck Street, Boston, MA 02115, USA

2 Informatics Program, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA

3 Current address: Stanford Neuroscience Program, Stanford University, Stanford CA 94305, USA

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BMC Medical Genomics 2013, 6:34  doi:10.1186/1755-8794-6-34

Published: 24 September 2013

Abstract

Background

Decades of research strongly suggest that the genetic etiology of autism spectrum disorders (ASDs) is heterogeneous. However, most published studies focus on group differences between cases and controls. In contrast, we hypothesized that the heterogeneity of the disorder could be characterized by identifying pathways for which individuals are outliers rather than pathways representative of shared group differences of the ASD diagnosis.

Methods

Two previously published blood gene expression data sets – the Translational Genetics Research Institute (TGen) dataset (70 cases and 60 unrelated controls) and the Simons Simplex Consortium (Simons) dataset (221 probands and 191 unaffected family members) – were analyzed. All individuals of each dataset were projected to biological pathways, and each sample’s Mahalanobis distance from a pooled centroid was calculated to compare the number of case and control outliers for each pathway.

Results

Analysis of a set of blood gene expression profiles from 70 ASD and 60 unrelated controls revealed three pathways whose outliers were significantly overrepresented in the ASD cases: neuron development including axonogenesis and neurite development (29% of ASD, 3% of control), nitric oxide signaling (29%, 3%), and skeletal development (27%, 3%). Overall, 50% of cases and 8% of controls were outliers in one of these three pathways, which could not be identified using group comparison or gene-level outlier methods. In an independently collected data set consisting of 221 ASD and 191 unaffected family members, outliers in the neurogenesis pathway were heavily biased towards cases (20.8% of ASD, 12.0% of control). Interestingly, neurogenesis outliers were more common among unaffected family members (Simons) than unrelated controls (TGen), but the statistical significance of this effect was marginal (Chi squared P < 0.09).

Conclusions

Unlike group difference approaches, our analysis identified the samples within the case and control groups that manifested each expression signal, and showed that outlier groups were distinct for each implicated pathway. Moreover, our results suggest that by seeking heterogeneity, pathway-based outlier analysis can reveal expression signals that are not apparent when considering only shared group differences.

Keywords:
Autism spectrum disorder; Blood gene expression; Nervous system development; Outliers; Pathways