Genetic analyses of the brain-derived neurotrophic factor (BDNF) gene in autism Katsuhiko Nishimura a,1 , Kazuhiko Nakamura a, * ,1 , A. Anitha a,1 , Kazuo Yamada b , Masatsugu Tsujii c,d , Yoshimi Iwayama b , Eiji Hattori b , Tomoko Toyota b , Nori Takei a , Taishi Miyachi d , Yasuhide Iwata a , Katsuaki Suzuki a , Hideo Matsuzaki e , Masayoshi Kawai a , Yoshimoto Sekine a , Kenji Tsuchiya a , Gen-ichi Sugihara d , Shiro Suda a , Yasuomi Ouchi d,f , Toshiro Sugiyama g , Takeo Yoshikawa b , Norio Mori a,d a Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan b Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan c Faculty of Sociology, Chukyo University, Toyota, Aichi, Japan d The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan e The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Graduate School of Medicine, Osaka University, Japan f The Positron Medical Center, Hamamatsu Medical Center, Hamamatsu, Japan g Aichi Children’s Health and Medical Center, Obu, Aichi, Japan Received 9 February 2007 Available online 5 March 2007 Abstract Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. Brain-derived neurotrophic factor (BDNF) plays a critical role in the pathogenesis of autism. In this study, we examined the SNP- and haplotypic-association of BDNF with autism in a trios-based association study (the Autism Genetic Resource Exchange). We also examined the expression of BDNF mRNA in the peripheral blood lymphocytes of drug-naı ¨ve autism patients and control subjects. In the TDT of autism trios, the SNP haplotype combinations showed significant associations in the autism group. BDNF expression in the drug-naı ¨ve autistic group was found to be significantly higher than in the control group. We suggest that BDNF has a possible role in the pathogenesis of autism through its neurotrophic effects on the serotonergic system. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Autism; Brain-derived neurotrophic factor; Serotonin transporter; A trios-based association; Peripheral blood lymphocytes Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repeti- tive behaviors that are detectable in early childhood. The serotonergic system has been found to be developmentally dysregulated in autism; factors that regulate serotonergic neuronal development and serotonin metabolism might have a crucial role in the pathophysiology of autistic disor- ders caused by the dysfunction of the serotonergic system [1]. Specifically, altered developmental dynamics of seroto- nin synthesis [2,3] and increases in whole blood serotonin levels have been reported in autistic individuals [4,5]. Effec- tive medications for treating autistic symptoms include drugs that have an impact on the serotonergic system, such as the serotonin receptor antagonists (e.g. Risperidone) and serotonin depleting agents (e.g. Fenfluramine) [6–8]. Multiple lines of evidence suggest that brain-derived neu- rotrophic factor (BDNF) plays a critical role in the seroto- nergic function. In the rat brain, BDNF has been found to promote the survival and sprouting of serotonergic axons [9] and the axonal growth of injured serotonergic neurons 0006-291X/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2007.02.135 * Corresponding author. Fax: +81 53 435 3621. E-mail address: nakamura@hama-med.ac.jp (K. Nakamura). 1 These authors contributed equally to this work. www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 356 (2007) 200–206