Ohiko Hashimoto

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.

Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population

Autistic patients have a 100 to 190‐fold increased risk of neurofibromatosis compared to the general population. This suggests that the two diseases may share a common etiological background. Recently, a new allele (or the six‐repeat allele) of the (AAAT)n repeat polymorphism in an Alu sequence in the neurofibromatosis‐1 (NF1) gene was observed exclusively in severe autistic patients, not in controls, in Caucasians of French ancestry. This suggests a role of the NF1 gene in the development of autism. We investigated three microsatellite polymorphisms within the intron‐27b and intron‐38 of the NF1 region, including the (AAAT)n and two (CA)n repeat polymorphisms, in Japanese subjects with autism (n = 74) and controls (n = 122). The six‐repeat allele of the (AAAT)n polymorphism was not found either in patients or controls, possibly indicating an ethnic difference in the polymorphism. However, significant differences were observed in the allele distributions of the (AAAT)n and a (CA)n, which were located at intron‐27b, between patients and controls, although an association was not significant between autism and another polymorphism at intron‐38. This may suggest an involvement of the NF1 locus in susceptibility to autism, although further investigations are recommended.

Delayed automatic detection of change in speech sounds in adults with autism: A magnetoencephalographic study

OBJECTIVE Autism is a form of pervasive developmental disorder in which dysfunction in interpersonal relationships and communication is fundamental. This study evaluated neurophysiological abnormalities at the basic level of language processing, i.e. automatic change detection of speech and non-speech sounds, using magnetoencephalographic recording of mismatch response elicited by change in vowels and tones. METHODS The auditory magnetic mismatch field (MMF) was evaluated in 9 adults with autism and 19 control subjects using whole-head magnetoencephalography. The MMF in response to the duration change of a pure tone or vowel /a/ and that in response to across-phoneme change between vowels /a/ and /o/, were recorded. RESULTS The groups were not significantly different in MMF power under any conditions. However, the autism group showed a left-biased latency prolongation of the MMF particularly under the across-phoneme change condition, and this latency delay was significantly associated with greater symptom severity. CONCLUSIONS These results suggest that adults with autism are associated with delayed processing for automatic change detection of speech sounds. These electrophysiological abnormalities at the earliest level of information processing may contribute to the basis for language deficits observed in autism. SIGNIFICANCE These results provide the first evidence for delayed latency of phonetic MMF in adults with autism.

Antenatal Depression and Maternal-Fetal Attachment

Background: In recent years, attention has been turned to maternal mental health in relation to the mother-child relationship accompanying a widening in focus, i.e. taking into account not only the puerperium, but also the stage of pregnancy. This applies to studies that have revealed a connection between depression and maternal attachment in the postpartum period and late pregnancy. This study, however, was designed to evaluate the maternal-fetal relationship in the first and second trimesters, being the first one to address this issue in these early stages. Sampling and Methods: Zung’s Self-Rating Depression Scale (ZSDS), the original Antenatal Maternal Attachment Scale (AMAS), and a questionnaire addressing peripheral factors were given to 216 pregnant women (3–6 months of gestation) who visited the Nagoya University Hospital between September 1998 and June 2001. Results: Contrary to reports on the latter stages of pregnancy, no direct association was observed between depression in mothers and maternal-fetal attachment before fetal movement was perceived. Conclusion: However, education, form of employment, planning of pregnancy, and premenstrual mood changes were found to be associated with the ZSDS score (mean: 41.9), while form of employment, feelings regarding pregnancy, and sources of support were extracted as factors associated with the AMAS, which are of interest in terms of the subsequent association between depression and maternal-fetal attachment in the peri- and postnatal periods.

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.

The NADH-ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene variants are associated with autism.

Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O, Jinde S, Nishida H, Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato N. The NADH‐ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene variants are associated with 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.

Gastrin-releasing peptide receptor (GRPR) locus in Japanese subjects with autism

Gastrin-releasing peptide receptor (GRPR) gene is considered a candidate locus for infantile autism for several reasons. The present study investigated two polymorphic sites (C/450/T and C/661/T) in the second exon of the GRPR gene in Japanese patients with autism (DSM-IV) and healthy subjects. The two polymorphic sites were at high linkage disequilirium, consistent with a previous study in a North American population. The C450-C661 allele, which was observed in one-third of the chromosomes from the North American subjects, was less frequent (6-7%) in the Japanese subjects, suggesting a large ethnic difference in the frequency of the polymorphism. The allele frequencies and genotype distributions were not significantly different between the patients and controls. However, further studies are required to exclude the GRPR locus as a candidate locus for autism, considering the low frequency of the polymorphism in the Japanese subjects.

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.