Shinko Koishi

Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population.

The oxytocin receptor (OXTR) gene, which is located on chromosome 3p25.3, has been implicated as a candidate gene for susceptibility of autism spectrum disorder (ASD). Positive associations between OXTR and ASD have been reported in earlier studies. However, the results were inconsistent and demand further studies. In this study, we investigated the associations between OXTR and ASD in a Japanese population by analyzing 11 single-nucleotide polymorphisms (SNPs) using both family-based association test (FBAT) and population-based case–control test. No significant signal was detected in the FBAT test. However, significant differences were observed in allelic frequencies of four SNPs, including rs2254298 between patients and controls. The risk allele of rs2254298 was ‘A’, which was consistent with the previous study in Chinese, and not with the observations in Caucasian. The difference in the risk allele of this SNP in previous studies might be attributable to an ethnic difference in the linkage disequilibrium structure between the Asians and Caucasians. In addition, haplotype analysis exhibits a significant association between a five-SNP haplotype and ASD, including rs22542898. In conclusion, our study might support that OXTR has a significant role in conferring the risk of ASD in the Japanese population.

Serotonin transporter gene promoter polymorphism and autism: A family-based genetic association study in Japanese population

Autism is now widely accepted as a biological disorder which, by and large, starts before birth. It has been shown that serotonin (5-HT) is associated with several psychological processes and hyperserotoninemia is observed in some autistic patients. The results of previous reports about family-based association studies between the serotonin transporter (5-HTT) gene promoter polymorphism and autism are controversial. In this study, an analysis using the transmission/disequilibrium test (TDT) between the 5-HTT gene promoter polymorphism and autism in 104 trios, all ethnically Japanese, showed no significant linkage disequilibrium (P=0.17). Recently, it has been reported that some haplotypes at the serotonin transporter locus may be associated with the pathogenesis of autism. Therefore, further investigations by haplotype analyses are necessary to confirm the implications of genetic variants of the serotonin transporter in the etiology of autism.

Association between autism and variants in the wingless-type MMTV integration site family member 2 ( WNT2 ) gene

Autism is a severe neurodevelopmental disorder with a complex genetic aetiology. The wingless-type MMTV integration site family member 2 (WNT2) gene has been considered as a candidate gene for autism. We conducted a case-control study and followed up with a transmission disequilibrium test (TDT) analysis to confirm replication of the significant results for the first time. We conducted a case-control study of nine single nucleotide polymorphisms (SNPs) within the WNT2 gene in 170 patients with autism and 214 normal controls in a Japanese population. We then conducted a TDT analysis in 98 autistic families (trios) to replicate the results of the case-control study. In the case-control study, three SNPs (rs3779547, rs4727847 and rs3729629), two major individual haplotypes (A-T-C and G-G-G, consisting of rs3779547, rs4727847, and rs3729629), and global probability values of the haplotype distributions in the same region (global p=0.0091) showed significant associations with autism. Furthermore, all of these significant associations were also observed in the TDT analysis. Our findings provide evidence for a significant association between WNT2 and autism. Considering the important role of the WNT2 gene in brain development, our results therefore indicate that the WNT2 gene is one of the strong candidate genes for autism.

No association of FOXP2 and PTPRZ1 on 7q31 with autism from the japanese population

Autism is a child-onset pervasive developmental disorder, with a significant role of genetic factors in its development. Genome-wide linkage studies have suggested a 7q region as a susceptibility locus for autism. We investigated several single nucleotide polymorphisms (SNPs) of Forkhead Box P2 (FOXP2) and Protein-Tyrosine Phosphatase, Receptor-type, Zeta-1 (PTPRZ1) at the 7q region in Japanese patients with autism and healthy controls. No significant difference was observed, after correction for the multiple testing, in allele, genotype or haplotype frequencies of the SNPs of FOXP2 or PTPRZ1 between patients and controls. No evidence was thus obtained for a major role of FOXP2 or PTPRZ1 in the development of autism.

No evidence for significant association between GABA receptor genes in chromosome 15q11-q13 and autism in a Japanese population

AbstractThe γ-aminobutyric acid (GABA) receptor genes GABRB3, GABRA5, and GABRG3 located on chromosome 15q11-q13 have been major candidates for susceptibility genes for autism, a neurodevelopmental disorder with a complex genetic etiology. In this study, we first investigated the association between the GABA receptor genes and autism in a Japanese population by analyzing 11 single nucleotide polymorphisms (SNPs). Intron 3 of GABRB3 was densely mapped because the previous studies observed the association of the microsatellite 155CA-2 located in the region. We observed no significant difference in allelic frequencies or genotypic distributions of the 11 SNPs between patients and controls. A permutation test showed no significant global differences in estimated haplotype frequencies between patients and controls. Analysis after confining the subjects to males showed similar results. Thus, this study provides no positive evidence of an association between the GABA receptor genes and autism in a Japanese population. However, in a SNP (rs3212337) located near the microsatellite 155CA-2, a significant deviation from the Hardy-Weinberg equilibrium was observed in patients (p = 0.029, corrected for multiple testing). This finding may suggest further studies around the markers for more definitive conclusions.

Association study of the 15q11-q13 maternal expression domain in Japanese autistic patients.

Chromosome 15q11‐q13 has been a focus of genetic studies of autism susceptibility, because cytogenetic abnormalities are frequently observed in this region in autistic patients. An imprinted, maternally expressed gene within the region may have a role in autistic symptomatology. In the present study, we investigated the association between autism and the maternal expression domain (MED) in the region, containing the UBE3A and ATP10C genes, and the upstream imprinting center (IC), which mediates coordinate control of imprinted expression throughout the region. We analyzed 41 single nucleotide polymorphisms (SNPs) in 166 patients with autism and 416 controls from a Japanese population. As a result, a statistically significant difference after correction for multiple testing was observed between the patients and controls in the genotypic distribution of SNP rs7164989 (SNP8 in this study) located in SNRPN, whose promoter corresponds to the IC (P = 0.018, corrected for multiple testing). In the analysis of a four‐marker haplotype located in ATP10C, a statistically significant difference after correction for multiple testing was observed in the frequency of one haplotype between male patients and controls (permutation P = 0.033, corrected for multiple testing). Thus, the present study may suggest the association between autism and the MED or the upstream IC in chromosome 15q11‐q13 in the Japanese population.

Tachykinin 1 (TAC1) gene SNPs and haplotypes with autism: A case-control study

Autism (MIM 209850) is a severe neurodevelopmental disorder characterized by disturbances in social interaction and communication, by repetitive body movements and restricted interests, and by atypical language development. Several twin and family studies have shown strong evidence for genetic factors in the etiology of autism. Glutamate is a major excitatory neurotransmitter in the human brain. Glutamate systems are involved in the pathophysiology of autism. There are many similarities between the symptoms evoked by glutamate antagonist treatment and symptoms of autism found in several human and animal studies. To elucidate the genetic background of autism, we analyzed the relationship between three single nucleotide polymorphisms (SNPs) of the Tachykinin 1 gene (TAC1) and autism, because TAC1 is located in the candidate region for autism and produces substance P and neurokinins. These products modulate glutamatergic excitatory synaptic transmission and are also involved in inflammation. Many different inflammation-related mechanisms could be involved in the autistic brain. Therefore, TAC1 may have some functions associated with the presumable pathophysiology of autism. We compared the allele and haplotype frequencies between autistic patients (n=170) and normal controls (n=214) in the Japanese population, but no significant difference was observed. Thus, the TAC1 locus is not likely to play a major role in the development of autism.

No association between the neuronal pentraxin II gene polymorphism and autism.

Autism (MIM 209850) is a neurodevelopmental disorder characterized by difficulties with verbal and non-verbal communication, impairments in reciprocal social interactions, and displays of stereotypic behaviors, interests and activities. Twin and family studies have indicated a robust role of genetic factors in the development of autism. Neuronal Pentraxin II (NPTX2) is located in chromosome 7q21.3-q22.1, where it is a candidate region for autism. NPTX2 promotes neuritic outgrowth and is suggested to mediate uptake of degraded synaptic material during synapse formation and remodeling. NPTX2 is also associated with the clustering of synaptic AMPA receptors. It was reported that glutamate systems including AMPA receptor was associated to the pathophysiology of autism. Thus, the NPTX2 gene is involved in neuritic outgrowth, synapse remodeling and the aggregation of neurotransmitter receptors at synapses. These functions play an important role in the mechanisms of learning and brain development. In the present study, we tested for the presence of the association of four single nucleotide polymorphisms (SNPs) of NPTX2 and haplotypes consisting of the SNPs with autism, between autistic patients (n=170) and normal controls (n=214) in a Japanese population. No significant difference was observed in the allele, genotype or haplotype frequencies between the patients and controls. Thus, the NPTX2 locus is not likely to play a major role in the development of autism. However, further studies with larger sample size and sequencing of NPTX2 gene are needed to exclude a role of NPTX2 gene in autism.

Notch4 gene polymorphisms are not associated with autism in Japanese population

Autism is a developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, occurring within the first 3 years of life. Several studies suggested that a disorder in the regulation of the growth of the central nervous system is associated with autism [Bailey et al., 1998]. But basic damages in the brain function in regard to this condition are hitherto unknown. Autism was formerly accepted as a child onset type of schizophrenia. Although they are now regarded as separate clinical entities, they share many clinical symptoms, such as indifference in human relationships, paucity of emotional expression, and behavioral eccentricity. In addition, among patients with juvenile onset schizophrenia, it has been reported that there were many who had a past history of autistic symptoms [Watkins et al., 1988]. Both diseases are thought to be multi-factorial by etiological studies, moreover, a linkage study suggested that there is a common candidate region between the two diseases [Auranen et al., 2002]. These facts point to the possibility that the two diseases might share some causal factors, thus it is interesting to further examine a comparison between the two diseases in genetic studies. Recently, genes in the Notch family were reported to be associated with the regulation of the development of the central nervous system [Uyttendaele et al., 1996; Sestan et al., 1999]. Furthermore, the Notch4 gene has been reported to be linked with vulnerability toward schizophrenia [Wei and Hemmings, 2000], although some subsequent studies have failed to replicate the results [McGinnis et al., 2001; Sklar et al., 2001; Ujike et al., 2001; Fan et al., 2002]. Based on these observations, we hypothesized that the Notch4 gene may be associated with autism. We report here the results of a case-control association study between autism and five polymorphisms within the HSMHC3A5 locus involving the Notch4 gene. Ninety five autistic patients fulfilled both DSM-IV [American Psychiatric Association, 1994] and ICD-10 DCR [World Health Organization, 1993] criteria (mean age SD, 17.38 10.39) and 95 unrelated healthy volunteers (mean age SD, 27.86 3.9) matched in gender (82 male and 13 female, M:F ratio1⁄4 6.3) were genotyped for the fivemarkers. Patients assessed in this study were recruited at the Outpatient Department of Tokai University hospital and two institutions for Autism. The volunteers, none of them had any mental illness defined in DSM-IV, were recruited from the staff and students of the Tokai University. All patients and controls were Japanese and ethnically homogeneous. These polymorphisms were the (TAA)n repeat, a T!C substitution (SNP1), an A!G substitution (SNP2) in the 50 flanking region, the (CTG)n repeat in exon 1 and the (TTAT)n repeat in intron 17 of the Notch4 gene. Genotyping and statistical analysis were carried out according to a previous report [Fan et al., 2002]. No significant differences in allele and genotype frequencies were observed between autistic patients and healthy volunteers (see Table I). In addition, there was no statistical significance between these two groups in haplotype analysis (data not shown). This is the first report to study the genetic association between autism and theNotch gene. These preliminary results do not support the role of the Notch4 gene in autism. However, further investigations of this and other genes (including theNotch family or someproteins *Correspondence to: Kenji Yamamoto, Department of Psychiatry and Behavioral Sciences, Tokai University School of Medicine; Bohseidai, Isehara, Kanagawa 259-1193, Japan. E-mail: key@is.icc.u-tokai.ac.jp

No association between the ryanodine receptor 3 gene and autism in a Japanese population

Aim:  Autism is a neurodevelopmental disorder with a complex genetic etiology. Chromosome 15q11‐q14 has been proposed to harbor a gene for autism susceptibility because deletion of the region leads to Prader‐Willi syndrome or Angelman syndrome, having phenotypic overlap with autism. Here we studied the association between autism and the ryanodine receptor 3 (RyR3) gene, which is located in the region. This is the first study, to our knowledge, that has investigated the association.