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Advancing the understanding of autism disease mechanisms through genetics

Abstract

Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.

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Figure 1: Genetic architecture of autism spectrum disorders.
Figure 2: Convergent neurobiological mechanisms in ASD.

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Acknowledgements

We thank members of the Geschwind laboratory for helpful discussions and critical reading of the manuscript. This work was supported by US National Institutes of Health (NIH) grants 5R37 MH060233 (D.H.G.), 5R01 MH094714 (D.H.G.) and K99MH102357 (J.L.S.), the California Institute for Regenerative Medicine (CIRM)–Broad Stem Cell Research Center (BSCRC) training grant TG2-01169 (L.d.l.T.-U.) and the Glenn–American Federation for Aging Research (AFAR) Postdoctoral Fellowship Program for Translational Research on Aging award 20145357 (H.W.).

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Supplementary information

Supplementary Table 1

Genetic contributions to autism. (XLSX 18 kb)

Supplementary Table 2

Mouse models of ASD. (XLSX 42 kb)

Supplementary Table 3

Human in vitro models of ASD. (XLSX 42 kb)

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de la Torre-Ubieta, L., Won, H., Stein, J. et al. Advancing the understanding of autism disease mechanisms through genetics. Nat Med 22, 345–361 (2016). https://doi.org/10.1038/nm.4071

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