Brain-Derived Neurotrophic Factor (BDNF) in autism. C. Correia1,2, A.M. Coutinho1, M. Barreto1,2, M. Martins1,2, L. Lourenço1,2, J. Almeida3, C. Marques3, T. S.Miguel4, A. Ataide4, G. Oliveira3, A.M. Vicente1,2 1) Instituto Gulbenkian Ciencia, Oeiras, Portugal; 2) Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal; 3) Hospital Pediátrico de Coimbra, Coimbra, Portugal; 4) Direcção Regional de Educação da Região Centro, Portugal.

   Several lines of evidence implicate BDNF, a neurotrophin crucial for brain development and function, in autism. In this study, the role of BDNF in autism etiology was studied. We found that BDNF plasma levels in autistic children (N=146) were significantly increased compared with control children (H=51.69, P<0.00001) and positively correlated with serotonin levels (r2=0.289; P=0.004), with an heritability of 30%. We therefore sought to identify genetic factors that might regulate BDNF distribution. Several candidate genes were assessed, including BDNF and its receptor NTRK2 genes; the HTR1A gene region, since the HTR1A serotonin receptor regulates serotonin levels; and the GAD1 gene, as it encodes a key regulator of glutamate which, neurotoxic when in excess, induces BDNF expression as a neuroprotective mechanism. We found an association of three markers in the HTR1A genomic region with BDNF levels (2=5.06, df=1, P=0.0245; 2=4.93, df=1, P=0.0264; 2=4.25, df=1, P=0.0392). While only one marker in this region showed a strong association with autism in the overall population (2=30.13, df=9, P=0.0004), the three markers associated with BDNF levels were also associated with autism in the subset of patients with high BDNF levels (Z=2.982, df=1, P=0.0029; Z=2.668, df=1, P=0.0076; Z=2.524, df=1, P=0.012). Unexpectedly these markers were located within RNF180, a recently identified gene mapping near HTR1A. RNF180 encodes a protein belonging to the zinc ring finger family implicated in the ubiquitination signal pathway, which is important in maintaining protein homeostasis and in transcriptional regulation by histone ubiquitination. Our results corroborate previous reports, in smaller cohorts, of increased plasma BDNF in autistic patients. The results also suggest that RNF180 may be involved in the regulation of BDNF levels through an as yet unexplained mechanism that may underlie autism etiology in a subset of patients.