title: Genetic analyses of roundabout (ROBO) axon guidance receptors in autism.
abstract: 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. One candidate SERT regulatory protein is the roundabout axon guidance molecule, ROBO. SerT expression in Drosophila is regulated by robo; it plays a vital role in mammalian neurodevelopment also. Here, we examined the associations of ROBO3 and ROBO4 with autism, in a trio association study using DNA from 252 families recruited to AGRE. 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 associations with autism; 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. We further compared the mRNA expressions of ROBO1, ROBO2, ROBO3, and ROBO4 in the lymphocytes of 19 drug-naïve autistic patients and 20 age- and sex-matched controls. 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. In conclusion, 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. To the best of our knowledge, this is the first report relating ROBO with autism.
authors.affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Anitha
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada
authors.forename: Shiro
authors.initials: S
authors.lastname: Suda
authors.forename: Ismail
authors.initials: I
authors.lastname: Thanseem
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Tsujii
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.forename: Eiji
authors.initials: E
authors.lastname: Hattori
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.forename: Taishi
authors.initials: T
authors.lastname: Miyachi
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Iwata
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Suzuki
authors.forename: Hideo
authors.initials: H
authors.lastname: Matsuzaki
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kawai
authors.forename: Yoshimoto
authors.initials: Y
authors.lastname: Sekine
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Gen-Ichi
authors.initials: G
authors.lastname: Sugihara
authors.forename: Yasuomi
authors.initials: Y
authors.lastname: Ouchi
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Keita
authors.initials: K
authors.lastname: Koizumi
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Higashida
authors.forename: Nori
authors.initials: N
authors.lastname: Takei
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Norio
authors.initials: N
authors.lastname: Mori
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D001321:Autistic Disorder / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008214:Lymphocytes; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000235:genetics*; D000097905:Roundabout Proteins
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins