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Peripheral blood gene expression signature differentiates children with autism from unaffected siblings

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Abstract

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental disorders with high heritability, yet a majority of genetic contribution to pathophysiology is not known. Siblings of individuals with ASD are at increased risk for ASD and autistic traits, but the genetic contribution for simplex families is estimated to be less when compared to multiplex families. To explore the genomic (dis-) similarity between proband and unaffected sibling in simplex families, we used genome-wide gene expression profiles of blood from 20 proband-unaffected sibling pairs and 18 unrelated control individuals. The global gene expression profiles of unaffected siblings were more similar to those from probands as they shared genetic and environmental background. A total of 189 genes were significantly differentially expressed between proband-sib pairs (nominal p < 0.01) after controlling for age, sex, and family effects. Probands and siblings were distinguished into two groups by cluster analysis with these genes. Overall, unaffected siblings were equally distant from the centroid of probands and from that of unrelated controls with the differentially expressed genes. Interestingly, five of 20 siblings had gene expression profiles that were more similar to unrelated controls than to their matched probands. In summary, we found a set of genes that distinguished probands from the unaffected siblings, and a subgroup of unaffected siblings who were more similar to probands. The pathways that characterized probands compared to siblings using peripheral blood gene expression profiles were the up-regulation of ribosomal, spliceosomal, and mitochondrial pathways, and the down-regulation of neuroreceptor-ligand, immune response and calcium signaling pathways. Further integrative study with structural genetic variations such as de novo mutations, rare variants, and copy number variations would clarify whether these transcriptomic changes are structural or environmental in origin.

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Acknowledgments

This work was supported by a grant from the Simons Foundation (SFARI 95117 to L.M.K. and I.S.K.), and NIH 5RO1MH085143 to L.M.K. We gratefully acknowledge all the participating families and their contributions. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. Approved researchers can obtain the SSC population dataset described in this study by applying at https://base.sfari.org. We are grateful to Heather Harris, Katherine Lowe, and coordinators and staff for the recruitment and comprehensive assessment of simplex families and Dr. Ronald Samuels, Jessica Yi, and Rachel Grant for recruiting the control individuals at Boston Children’s Hospital.

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Authors and Affiliations

  1. Informatics Program at the Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston Children’s Hospital, Boston, MA, 02115, USA

    S. W. Kong, M. G. Campbell, I. H. Lee & I. S. Kohane

  2. Division of Genetics, Program in Genomics, Boston Children’s Hospital, Boston, MA, 02115, USA

    Y. Shimizu-Motohashi, C. D. Collins, S. J. Brewster, I. A. Holm & L. M. Kunkel

  3. Division of Developmental Medicine, Boston Children’s Hospital, Boston, MA, 02115, USA

    L. Rappaport

  4. Center for Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA

    I. S. Kohane

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  1. S. W. Kong
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  2. Y. Shimizu-Motohashi
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  3. M. G. Campbell
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  4. I. H. Lee
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  5. C. D. Collins
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  6. S. J. Brewster
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  7. I. A. Holm
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  8. L. Rappaport
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  9. I. S. Kohane
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  10. L. M. Kunkel
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Corresponding author

Correspondence to L. M. Kunkel.

Additional information

S.W. Kong and Y. Shimizu-Motohashi contributed equally to this work.

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Kong, S.W., Shimizu-Motohashi, Y., Campbell, M.G. et al. Peripheral blood gene expression signature differentiates children with autism from unaffected siblings. Neurogenetics 14, 143–152 (2013). https://doi.org/10.1007/s10048-013-0363-z

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  • DOI: https://doi.org/10.1007/s10048-013-0363-z

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