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Two clock genes associated with Autistic Disorder: a molecular genetics study prompted by clinical observations of communicative timing in autism. D. Wimpory1&2 and B. Nicholas3 Reporting on collaborative work published* with S. Nash2, V. Rudrasingham4, G. Kirov4 and M.J. Owen4 1Department of Psychology (Specialist Children’s Services), North West Wales NHS Trust, 2School of Psychology, Bangor University,3North West Cancer Research Fund Institute, Bangor University, and 4Department of Psychological Medicine, Cardiff University. Background Data from evaluated NHS clinical assessment and intervention indicate that communicative timing is an important aspect of the interaction difficulties experienced by people with Autistic Disorder. Communicative timing, sleep patterns and emotional contextual memory are affected in Autistic Disorder. Research in mammals and insects shows that clock genes regulate communicative timing, sleep and emotional contextual memory. Genetics studies indicate that a number of genes, some interacting, are affected in Autism. Aim To test the hypothesis that variations in the clock genes per1, per2, per3, clock, npas2, bmal1, tim, cry1, cry2, dbp and ck1e are associated with Autistic Disorder. Methods 11 clock genes were examined in 110 parent-child trios where progenies had strictly diagnosed Autistic Disorder without substantial learning disability. We tested for association of clock gene variants with Autistic Disorder by genotyping the parents and their affected children. We recorded the transmission of the clock gene markers from the parents to the autistic children and calculated how the transmission of the clock gene markers in the autism families compared with the transmission frequencies normally expected for these markers. * Association of Per1 and Npas2 with autistic disorder: support for the clock genes/social timing hypothesis Nicholas, B, Rudrasingham, V, Nash, S, Kirov, G, Owen, M.J and Wimpory, D (corresponding author), Mol Psychiatry. 2007 Jun;12(6):581-92. Results Summary We found significant association (P< 0.05) for four markers in two clock genes; two in per1 (17p) and two in npas2 (2q). Haplotype analysis of all our markers in per1 and in npas2 gave a best result of p<0.027 for per1 and p<0.001 for npas2. Fig.1 Fig.1 shows the approximate location of the two significant markers in per1, one in intron 12 and the other in the 3’ UTR. Conclusions This is the first time that variations in interacting and behaviour modulating genes from the same biochemical pathway are shown to be associated with Autistic disorder and our results support the hypothesis that the clock genes per1 and npas2 may be involved in Autistic Disorder’s aetiology. Problems in timing, sleep and memory are all characteristics of autism and aspects of timing, sleep and memory are each clock-gene-regulated in other species. Our findings have relevance to explanations of autism that focus on the amygdala, cerebellum, memory and temporal deficits. They offer support for the evaluation of clinical practice involving chronotherapies. These include melatonin to address sleep patterns and Musical Interaction Therapy to address temporal synchrony/timing in communication and related developments. The study highlights the value of clinicallyinformed empirical work with feedback for clinical practice. Abbreviations per1: per gene, human homologue of the Drosophila PERIOD gene npas2: gene for Neuronal PAS Domain Protein