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Association of Per1 and Npas2 with autistic disorder: support for the clock genes/social timing hypothesis

Molecular Psychiatry volume 12, pages 581–592 (2007)Cite this article

Abstract

Clock gene anomalies have been suggested as causative factors in autism. We screened eleven clock/clock-related genes in a predominantly high-functioning Autism Genetic Resource Exchange sample of strictly diagnosed autistic disorder progeny and their parents (110 trios) for association of clock gene variants with autistic disorder. We found significant association (P<0.05) for two single-nucleotide polymorphisms in per1 and two in npas2. Analysis of all possible combinations of two-marker haplotypes for each gene showed that in npas2 40 out of the 136 possible two-marker combinations were significant at the P<0.05 level, with the best result between markers rs1811399 and rs2117714, P=0.001. Haplotype analysis within per1 gave a single significant result: a global P=0.027 for the markers rs2253820–rs885747. No two-marker haplotype was significant in any of the other genes, despite the large number of tests performed. Our findings support the hypothesis that these epistatic clock genes may be involved in the etiology of autistic disorder. Problems in sleep, memory and timing are all characteristics of autistic disorder and aspects of sleep, memory and timing are each clock-gene-regulated in other species. We identify how our findings may be relevant to theories of autism that focus on the amygdala, cerebellum, memory and temporal deficits. We outline possible implications of these findings for developmental models of autism involving temporal synchrony/social timing.

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Acknowledgements

We gratefully acknowledge the North West Wales NHS Trust that salaried our Principal Investigator (PI), Dawn Wimpory, throughout the duration of this research. We are most appreciative of The Baily Thomas Charitable Fund for their financial facilitation of the project with additional funding from Autism Cymru. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Cure Autism Now and is supported, in part, by Grant MH64547 from the National Institute of Mental Health to Daniel H Geschwind (PI). In addition, we thank Professor Vishwajit L Nimgaonkar, University of Pittsburgh School of Medicine, who supplied us with details on SNPs in clock genes that were identified in his laboratory. We particularly thank Professor William Fraser for his enthusiasm and advice, together with Professor Elizabeth Newson, OBE, for her original and inspiring clinical insight.

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Authors and Affiliations

  1. North West Cancer Research Fund Institute, University of Wales, Bangor, UK

    B Nicholas

  2. Department of Psychological Medicine, Cardiff University, Cardiff, UK

    V Rudrasingham & M J Owen

  3. School of Psychology, University of Wales, Bangor, UK

    S Nash & D C Wimpory

  4. Specialist Children's Services, North West Wales NHS Trust, Bangor, UK

    G Kirov & D C Wimpory

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  1. B Nicholas
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  2. V Rudrasingham
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  3. S Nash
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  5. M J Owen
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  6. D C Wimpory
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Correspondence to D C Wimpory.

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Nicholas, B., Rudrasingham, V., Nash, S. et al. Association of Per1 and Npas2 with autistic disorder: support for the clock genes/social timing hypothesis. Mol Psychiatry 12, 581–592 (2007). https://doi.org/10.1038/sj.mp.4001953

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  • DOI: https://doi.org/10.1038/sj.mp.4001953

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