Browsing by Author "Skuse, D."
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- Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum DisordersPublication . Leblond, C.S.; Heinrich, J.; Delorme, R.; Proepper, C.; Betancur, C.; Huguet, G.; Konyukh, M.; Chaste, P.; Ey, E.; Rastam, M.; Anckarsäter, H.; Nygren, G.; Gillberg, I.C.; Melke, J.; Toro, R.; Regnault, B.; Fauchereau, F.; Mercati, O.; Lemière, N.; Skuse, D.; Poot, M.; Holt, R.; Monaco, A.P.; Järvelä, I.; Kantojärvi, K.; Vanhala, R.; Curran, S.; Collier, D.A.; Bolton, P.; Chiocchetti, A; Klauck, S.M.; Poustka, F.; Freitag, C.M.; Waltes, R.; Kopp, M.; Duketis, E.; Bacchelli, E.; Minopoli, F.; Ruta, L.; Battaglia, A.; Mazzone, L.; Maestrini, E.; Sequeira, A.F.; Oliveira, B.; Vicente, A.M.; Oliveira, G.; Pinto, D.; Scherer, S.W.; Zelenika, D.; Delepine, M.; Lathrop, M.; Bonneau, D.; Guinchat, V.; Devillard, F.; Assouline, B.; Mouren, M.C.; Leboyer, M.; Gillberg, C.; Boeckers, T.M.Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
- Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: genetic and molecular studiesPublication . Tansey, K.E.; Brookes, K.J.; Hill, M.J.; Cochrane, L.E.; Gill, M.; Skuse, D.; Correia, C.; Vicente, A.M.; Kent, L.; Gallagher, L.; Anney, R.J.Oxytocin (OXT) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. It is postulated that OXT reduces activation of the amygdala, inhibiting social anxiety, indicating a neural mechanism for the effects of OXT in social cognition. Genetic variation at the oxytocin receptor gene (OXTR) has been reported to be associated with autism. We examined 18 SNPs at the OXTR gene for association in three independent autism samples from Ireland, Portugal and the United Kingdom. We investigated cis-acting genetic effects on OXTR expression in lymphocytes and amygdala region of the brain using an allelic expression imbalance (AEI) assay and by investigating the correlation between RNA levels and genotype in the amygdala region. No marker survived multiple correction for association with autism in any sample or in a combined sample (n=436). Results from the AEI assay performed in the lymphoblast cell lines highlighted two SNPs associated with relative allelic abundance in OXTR (rs237897 and rs237895). Two SNPs were found to be effecting cis-acting variation through AEI in the amygdala. One was weakly correlated with total gene expression (rs13316193) and the other was highlighted in the lymphoblast cell lines (rs237895). Data presented here does not support the role of common genetic variation in OXTR in the aetiology of autism spectrum disorders in Caucasian samples.