Genetic analyses of serotonergic factors in autism

Kazuhiko Nakamura, MD, PhD1, Anitha Ayyappan, PhD1, Kazuo Yamada, MD, PhD2, Shiro Suda, MD, PhD1, Masatsugu Tsujii, PhD3, Yoshimi Iwayama, PhD2, Taishi Miyachi, MD, PhD4, Hideo Matsuzaki, MD, PhD5, Kenji Tsuchiya, MD, PhD4, Toshiro Sugiyama, MD, PhD6, Nori Takei, MD, PhD4, Takeo Yoshikawa, MD, PhD2, and Norio Mori, MD, PhD1. (1) Psychiatry and Neurology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan, (2) Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan, (3) Faculty of Sociology, Chukyo University, 101-Tokodate Kaizu-cho, Toyota, Aichi, 470-0393, Japan, (4) The Osaka-Hamamatsu Joint Reserach Center for Child Mental Development, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan, (5) The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan, (6) Aichi Chilren's Health and Medical Center, 1-2 Osakada Morioka-cho, Obu, Aichi, 474-8710, Japan

Background: autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (SERT) modulates serotonin levels, and is a major therapeutic target in autism. Factors that regulate SERT expression might be implicated in the pathophysiology of autism.

Objectives: SERT expression in Drosophila is reported to be regulated by the roundabout axon guidance molecule, robo; ROBO proteins (ROBO1, 2, 3, and 4) play a vital role in mammalian neurodevelopment also. We examined the associations of ROBO genes with autism, in a trios association study. Further, we compared the mRNA expressions of ROBO genes in the autistic patients and control subjects.

Methods: DNA samples from trio families recruited to the AGRE were used for this study; 252 trio families, with male offspring scored for autism, were selected. Genotypes were determined in ABI PRISM 7900HT Sequence Detection System. One-way analysis of variance was used to examine the variability in the distribution of ADI-R phenotypic data. We further compared the mRNA expressions of ROBO genes in the lymphocytes of 19 drug-naïve autistic patients and 20 matched controls.

Results: four SNPs of ROBO3 (rs3923890, p=0.023; rs7925879, p=0.017; rs4606490, p=0.033 and rs3802905, p=0.049) and a single SNP of ROBO4 (rs6590109, p=0.009) showed significant associations with autism, by transmission disequilibrium test; the A/A genotype of rs3923890 showed lower ADI-R_A scores, which reflect social interaction. Significant haplotype associations were also observed for ROBO3 and ROBO4. Expressions of ROBO1 (p=0.018) and ROBO2 (p=0.023) were significantly reduced in the autistic group; the possibility of using the altered expressions of ROBO as peripheral markers for autism, may be explored.

Conclusions:we suggest a possible role of ROBO in the pathogenesis of autism. Abnormalities of ROBO may lead to autism either by interfering with serotonergic system, or by disrupting neurodevelopment.


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