Abstract
Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 51-56 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 520 |
| Issue number | 7545 |
| DOIs | |
| State | Published - Apr 2 2015 |
Funding
Acknowledgements We acknowledge the participation of all of the families in the AGRE, NIMH and SSC studies that have been a model of public participatory research. The AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health. The SSC used here was developed by the following principal investigators: A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, E. Wijsman. We thank the Allen Brain Atlas for use of their publicly available developing human brain expression data. Finally, we thank V. Kustanovich (AGRE) for helping with access to Autism Diagnostic Observation Schedule severity score data, D. Arking for sharing DNA from the SSC for Taqmangenotyping,S.Maragh for zebrafish complementary DNA (cDNA)librariesand eef1a1l1 primers, A. Kapoor for discussions, Q. Jiang for the translation of ref. 43, and J.A.Rosenfeld,L.G.Shaffer,Y.Shenand B.-L.Wufor sharingCNVdatasets.Sequencing services were provided by the Johns Hopkins University Next Generation Sequencing Center, Sidney Kimmel Comprehensive Cancer Center, Illumina Sequencing Services and the Johns Hopkins University Genetic Resources Core Facility. E.C.O. is a National Alliance for Research on Schizophrenia and Depression young investigator. N.K. is a Distinguished George W. Brumley Professor. This work was funded by grants from the Simons Foundation to A.C. and to N.K., NIMH grant MH095867 to M.E.T., NIMH grants 5R25MH071584-07 and MH19961-14 to D.M.D.L. (Malison), National Institutes of Health grant RO1MH074090 to C.L.M., NIMH grant R01MH081754 to A.C. and an Autism Speaks Dennis Weatherstone pre-doctoral fellowship (number 7863) to T.T.
ASJC Scopus subject areas
- General