The DOI matches its Crossref record; 57 of the 59 references it cites were found in a registry or an index; none of the 22 sources its claims cite is checked for support yet.
Two genetic variants of CD38 in subjects with autism spectrum disorder and controls
Open accessAbstract
The neurobiological basis of autism spectrum disorder (ASD) remains poorly understood. Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons. In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p<0.040) and rs3796863 (p<0.005) showed significant associations with a subset of ASD (IQ>70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD.
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TL;DR
This study examined CD38 variants in autism spectrum disorder (ASD), finding that CD38 colocalizes with oxytocin in human hypothalamic neurons and that two CD38 polymorphisms were associated with high-functioning autism in U.S. AGRE trios but not Japanese HFA trios. A rare R140W mutation was linked to lower plasma oxytocin in a small subset and one carrier reportedly improved on intranasal oxytocin.
Key findings
- CD38 immunoreactivity colocalized extensively with oxytocin in the paraventricular nucleus of the human hypothalamus; highest CD38 expression was in hypothalamus, with substantial expression in frontal cortex, amygdala, and cerebellum.
- In U.S. AGRE HFA trios (IQ>70; 104 trios), rs6449197 (p=0.040) and rs3796863 (p=0.005) were significantly associated with ASD; rs3796863 showed only a tendency in all 252 AGRE trios (p=0.088), and no association was detected in 188 Japanese HFA trios (p=0.228). The second haplotype block (SNPs06–07) showed strong association in HFA trios (p=0.001), with the CT haplotype significant after permutation (p=0.005; overtransmitted 69.18%).
- The R140W mutation (rs1800561, 4693C>T) was found in 0.6%–4.6% of the Japanese population; in cohort 2, 13/301 ASD subjects were heterozygous (allelic frequency 0.022) versus 17/417 controls heterozygous plus one homozygous (allelic frequency 0.023), and the association was not replicated (χ2=1.20, p<0.3). In three families, 18 R140W carriers were identified, 8 of whom had ASD or ASD traits (44%), and no ASD subjects were found without the mutant SNP.
- Plasma oxytocin was lower in ASD probands with the W140 allele (79.3 ± 14.9 pg/ml; n=3) than in ASD subjects without it (147.7 ± 15.0 pg/ml; p<0.01; n=26) and controls with R140 (198.2 ± 24.7 pg/ml; p<0.01; n=100); AVP was slightly higher in W140 probands (38.9 ± 3.8 vs 26.9 ± 5.0 pg/ml; p<0.05). One 23-year-old proband with the W140 allele received nasal oxytocin and showed maintained improvement for more than 20 months.
Methods
- Immunohistochemistry and RT-PCR were used on post-mortem human brain tissue to assess CD38 expression and colocalization with oxytocin, including hypothalamic paraventricular nucleus and insular cortex as control.
- Genetic analyses included 10 intronic SNPs and exonic mutation screening of CD38 across Japanese case-control cohorts (29 ASD/315 controls; 301 ASD/417 controls), 188 Japanese HFA trios, 16 Korean ASD/150 controls, 252 AGRE trios including 104 U.S. HFA trios, plus Russian and Italian samples; analyses used FBAT, TDT, haplotype tests, ANOVA, and permutation.
- Plasma oxytocin and vasopressin were measured by enzyme immunoassay; ASD traits in relatives were assessed with the Autism-Spectrum Quotient (AQ), and one proband received intranasal oxytocin.
Limitations
- The paper states “despite their statistical limitations” and calls for functional and expression assays to assess biological effects of the variants, as well as further systematic case-control investigations to verify oxytocin treatment effects.
- The association findings did not replicate in Japanese HFA trios or in the larger Japanese R140W case-control cohort, and the functional importance of the intronic rs3796863 SNP “remains to be determined.”
- Evident from the text: plasma oxytocin comparisons for W140 carriers relied on very small numbers (n=3 ASD probands; only one control W140 carrier), the intranasal oxytocin report is a single uncontrolled proband, and the structural analysis is described as preliminary.
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50 Own result · 12 Not checked yet · 9 Own interpretation · 7 Own method · 1 No basis given
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In the paper
“An association study for 10 intronic SNPs shown in Fig. 2 was first performed in a case-control study in a Japanese population (29 ASD subjects and 315 controls, the first cohort in the Table 1).No significant association with ASD was found for these SNPs (data not shown).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.1. Intronic SNP analysis in Japanese and U.S. subjects
plainn = 29- Asserted: passes — The authors put it forward as true.
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In the paper
“Unlike the U.S. cases, no association was detected in 188 Japanese HFA trio cases selected from cohort 2 (p=0.228).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.1. Intronic SNP analysis in Japanese and U.S. subjects
plainn = 188- Asserted: passes — The authors put it forward as true.
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“Linkage disequilibrium (LD) analysis identified three haplotype blocks across the CD38 gene in 104 trios in AGRE samples, with the first block comprising SNPs01-05, the second block comprising SNPs06 and 07, and the third block comprising SNPs08 and 09 (Fig. 4).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.1. Intronic SNP analysis in Japanese and U.S. subjects
plainn = 104- Asserted: passes — The authors put it forward as true.
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In the paper
“In the FBAT of HFA trios, rs6449197 (p=0.040) and rs3796863 (p=0.005)showed significant associations”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.1. Intronic SNP analysis in Japanese and U.S. subjects
plaincorrelationaln = 104 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“In the FBAT of HFA trios, rs6449197 (p=0.040) and rs3796863 (p=0.005)showed significant associations”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.1. Intronic SNP analysis in Japanese and U.S. subjects
plaincorrelationaln = 104 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Again, none of the SNPs showed significant associations, except rs3796863 (SNP06) with a tendency toward association (p=0.088;Table 4).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.1. Intronic SNP analysis in Japanese and U.S. subjects
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Following post hoc pairwise comparison with the Bonferroni method, the variations in the distribution of ADI-R_C between the C/C and C/A groups were found to be significant at the 0.05-and 0.01-levels, in the 252 and HFA trios, respectively.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.1. Intronic SNP analysis in Japanese and U.S. subjects
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“CD38 immunoreactivity was detected in the hypothalamus of the two Japanese brains (data not shown).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3. Results
plainn = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons.”
- Also stated in: § 3. Results · plain
“double immunohistochemical staining revealed high levels of CD38 immunoreactivity in many cells in the paraventricular nucleus of the hypothalamus and showed extensive colabeling with OT”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > Abstract
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- Also stated in: § 3. Results · plain
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In the paper
“A weak association was detected for rs1800561 (R140W) in adult ASD patients”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.2. Mutation analysis
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The highest level of CD38 expression was detected in the human hypothalamus, and we detected substantial expression in the frontal cortex, amygdala, and cerebellum (data not shown).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3. Results
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“One-way ANOVA showed a significant variation in the distribution of ADI-R_C scores (restricted, repetitive, and stereotyped patterns of behavior) between the C/C, C/A, and A/A genotypes of SNP06 of CD38, in 252 trios (p=0.013) and HFA trios (p=0.0067) (Fig. 3).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.1. Intronic SNP analysis in Japanese and U.S. subjects
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The haplotypes GGCAG (p=0.022) and GGTAG (p=0.034) of this block showed significant associations; however, this was not significant by permutation (permutation p=0.157 for GGCAG and permutation p=0.271 for GGTAG).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.1. Intronic SNP analysis in Japanese and U.S. subjects
plaincorrelationaln = 104 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“In this block, the haplotypes AT (p=0.015) and CT (p=0.0007)showed significant associations; the association shown by CT remained significant (permutation p=0.005), while that of AT was not significant (permutation p=0.12), by permutation.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.1. Intronic SNP analysis in Japanese and U.S. subjects
plaincorrelationaln = 104- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, although we detected the SNP in 5 of the 150 Korean controls, it was not detected it among the 16 Korean patients (cohort 3 in Table 1) or the 263 Caucasian patients (cohort 4 in Table 1).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.2. Mutation analysis
plainn = 16- Asserted: passes — The authors put it forward as true.
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In the paper
“The haplotypes of the 3 rd haploblock, which included SNPs 08 and 09, did not show any association with HFA.None of the haplotypes in the 252 trios showed significant association.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.1. Intronic SNP analysis in Japanese and U.S. subjects
plain- Asserted: passes — The authors put it forward as true.
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“The immediate effect of OT was obvious after the first trial, in which he was no longer boisterous after awaking early in the morning.This quieting on awaking has been maintained for more than 20 months.He showed improvements in eye contact behavior with smiling and answering to yes/no questions in his daily life.There were no significant adverse effects.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 3.4. Plasma OT and vasopressin levels
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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“The mutant structure is more open and has a slightly larger degree of variation (Fig. 7C and E).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 4. Discussion
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In the paper
“The mutant structure has a more the open conformation than the wild-type and a slightly larger degree of variation.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 4. Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The predicted protein structures and molecular dynamics simulations accurately reflect the actual structural and dynamic properties of W140-CD38.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The W140 protein has an outward conformation and fewer interacting residues than the wild-type protein.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 4. Discussion
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The predicted protein structures and molecular dynamics simulations accurately reflect the actual structural and dynamic properties of W140-CD38.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Amino acid sequence of CD38 showing conservation of R at the 140th amino acid among different species, except for rodents and rabbits.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 4. Discussion
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In the paper
“R140 and W140 are packed into the helix, and the packing conformation seems stable.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 4. Discussion
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The predicted protein structures and molecular dynamics simulations accurately reflect the actual structural and dynamic properties of W140-CD38.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, taking into account the results that the W140 allele is not associated with ASD in general population, we can only say that the W140 allele is deemed to have a role in decreased plasma OT levels, but not in AVP levels, regardless of disease status.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 4. Discussion
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In the paper
“Based on the results of SNP-and haplotype-TDT analyses, the A allele of rs3796863 of CD38 may be considered a protective allele and the C allele as a risk allele for U.S. HFA cases.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 4. Discussion
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In the paper
“Oxytocin (OT) is secreted into the brain by hypothalamic neuronal dendrites and plays important roles in social recognition and memory (Insel & Fernald, 2004;Takayanagi et al., 2005;Donaldson et al., 2008;Neumann, 2008).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 1. Introduction
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In the paper
“Peripheral or nasal administration of OT facilitates social recognition and trust in healthy humans (Guastella et al., 2008a andb, 2009;Ditzen et al., 2009) and increases eye contact and recognition in autistic subjects (Hollander et al., 2007;Yamasue et al., 2009).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 1. Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The use of this tissue followed the institutional guidelines established by the Committee on Human Research (CHR) in both universities.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 2.1. CD38 expression and immunohistochemistry
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In the paper
“The diagnoses were made by two experienced child psychiatrists through interviews and clinical record reviews, and the subjects had no apparent physical anomalies.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 2.1. CD38 expression and immunohistochemistry
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In the paper
“The CD38 gene consists of 8 exons on 4p15 (Nakagawa et al., 1995) and spans a genomic stretch of 70.51 kb.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 1. Introduction
What the sources say
- Not checked yetcites Nakagawa et al., 1995
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In the paper
“Additional selection criteria required that (i) there be no possible non-idiopathic autism flags and (ii) all the trios be Whites, with the exclusion of Hispanic and Latino races (Anita et al., 2008).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 2.1. CD38 expression and immunohistochemistry
What the sources say
- Not checked yetcites Anita et al., 2008
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In the paper
“In the Japanese cohorts, all subjects resided in Kanazawa, Hamamatsu/Nagoya, Tokyo, or Osaka, Japan, and all patients and controls were Japanese with no non-Japanese parents or grandparents.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 2.1. CD38 expression and immunohistochemistry
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In the paper
“Human CD38 is a type II transmembrane antigen (Malavasi et al., 2008).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 1. Introduction
What the sources say
- Not checked yetcites Malavasi et al., 2008 source
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“CD38 is expressed in the brain (Lee, 2001;Higashida et al., 2007) and can catalyze the formation of cyclic ADP-ribose (cADPR) from NAD + (Lee, 2001;Guse, 2005;Malvasi et al., 2008).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 1. Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This study was approved by the ethics committees of Kanazawa University, Hamamatsu Medical University, University of Tokyo, Osaka University, RIKEN, and the other participating institutes.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 2.1. CD38 expression and immunohistochemistry
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Two experienced child psychiatrists independently confirmed the diagnosis of ASD for most patients by semi-structured behavior observation and interviews with the subjects and their parents.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 2.1. CD38 expression and immunohistochemistry
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“PedCheck program v1.1 (http://watson.hgen.pitt.edu)was used to identify and eliminate all Mendelian inheritance inconsistencies in the trio genotype data.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 2.6. Statistics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“cADPR mobilizes Ca 2+ from intracellular Ca 2+ stores, thus acting as a second messenger (Lee, 2001).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 1. Introduction
What the sources say
- Not checked yetcites Lee, 2001 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“They showed that CD38 regulates OT secretion in the mouse hypothalamus and posterior pituitary, which is critical for mouse social behavior (Jin et al., 2007;Liu et al., 2008).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 1. Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In conclusion, despite their statistical limitations, our results suggest that the rs3796863 SNP may contribute to genetic susceptibility to HFA in U.S. but not necessarily in Japanese subjects (at least to the limits of our current analysis).”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 4. Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The association between rs3796863 and HFA in U.S. trios is not due to population stratification or other confounding that would produce a spurious association.
The authors state this as an assumption.
The precise role of CD38 in the human hypothalamus was not clarified before this study.
“The precise role of CD38 in the human hypothalamus, however, has not been clarified.”
The authors state this as an assumption.
The effects of long-term OT treatment on human social behavior in ASD patients were unknown before this study.
“Those observations are based mostly on a small number of administrations, and the effects of long-term OT treatment on human social behavior in ASD patients is unknown.”
The paper relies on this without support.
The unscreened control subjects in cohort 2 were free of ASD.
“In 417 unscreened control subjects without ASD, 10 males and 7 females were heterozygous for the mutation and one female was homozygous (allelic frequency, 0.023).”
The paper relies on this without support.
The association between rs3796863 and HFA in U.S. trios is not due to population stratification or other confounding that would produce a spurious association.
“In conclusion, despite their statistical limitations, our results suggest that the rs3796863 SNP may contribute to genetic susceptibility to HFA in U.S. but not necessarily in Japanese subjects (at least to the limits of our current analysis).”
The paper relies on this without support.
The CHO cell and Cd38 null mouse models used in the cited studies are valid models for human W140-CD38 function.
“In CHO cells, in fact, the W140-CD38 protein possesses only one third of the ADP-ribosyl cyclase activity of R140-CD38 (Yagui et al., 1998).Moreover, social amnesia was not rescued by local re-expression of human W140-CD38 in the hypothalamus in the Cd38 null mice (Jin et al., 2007).”
The paper relies on this without support.
The predicted protein structures and molecular dynamics simulations accurately reflect the actual structural and dynamic properties of W140-CD38.
“The mutant structure has a more the open conformation than the wild-type and a slightly larger degree of variation.”
The paper relies on this without support.
Low blood oxytocin levels in ASD patients reflect central oxytocin function relevant to social behavior.
“Furthermore, the W140 allele could be a potential risk factor for a subset of Japanese ASD patients, i.e., males with low blood OT levels.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Therefore, the R140W mutation causes significant modifications and damage to the predicted protein structure in comparison with the human wild-type (R140) CD38 (see Fig. 7 of Munesue et al., 2010).”
From CD38 and its role in oxytocin secretion and social behavior (2012) · cites this paper as Munesue et al., 2010
In the citing paper
“The highest level of CD38 was found in the hypothalamus (Munesue et al., 2010).”
From CD38 and its role in oxytocin secretion and social behavior (2012) · cites this paper as Munesue et al., 2010
In the citing paper
“Our preliminary studies suggest that a subgroup of ASD subjects with the R140W SNP and intelligence impairments may be effectively treated with OXT (Munesue et al., 2010)”
From CD38 and its role in oxytocin secretion and social behavior (2012) · cites this paper as Munesue et al., 2010
In the citing paper
“The OXT plasma concentrations of the five R140W carriers (79.2 ± 16.6 pg/ml; n = 5; Munesue et al., 2010) were lower than those of ASD subjects lacking the mutation (147.7 ± 15.0 pg/ml; p < 0.01; n = 26).”
From CD38 and its role in oxytocin secretion and social behavior (2012) · cites this paper as Munesue et al., 2010
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 1. Introduction
“We measured the carrier's serum OT levels and examined each subject for ASD.”
§ Two genetic variants of CD38 in subjects with autism spectrum disorder and controls > 2.5. Enzyme immunoassay for OT and vasopressin
“The samples were centrifuged at 0°C at 2,600 x g for 15 min and the plasma was separated off, divided into 2 tubes, and stored at -80°C.We performed the peptide assay for OT and vasopressin (AVP) as described previously (Jin et al., 2007;Liu et al., 2008).”
Citations
Cites
Lord, C., Rutter, M., & Le Couteur, A. (1994) · Journal of Autism and Developmental Disorders · doi:10.1007/bf02172145 · Cited by 9,065
Oxytocin increases trust in humans
Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U., & Fehr, E. (2005) · Nature · doi:10.1038/nature03701 · Cited by 3,690
Strong association of de novo copy number mutations with autism
Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., et al. (2007) · Science · doi:10.1126/science.1138659 · Cited by 2,795
Baird, G., Simonoff, E., Pickles, A., Chandler, S., Loucas, T., Meldrum, D., & Charman, T. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69041-7 · Cited by 2,104
Oxytocin, vasopressin, and the neurogenetics of sociality
Donaldson, Z. R., & Young, L. J. (2008) · Science · doi:10.1126/science.1158668 · Cited by 1,645
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes
Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S., Zhang, H., Estes, A., Brune, C. W., Bradfield, J. P., et al. (2009) · Nature · doi:10.1038/nature07953 · Cited by 1,421
Oxytocin improves “mind-reading” in humans
Domes, G., Heinrichs, M., Michel, A., Berger, C., & Herpertz, S. C. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.07.015 · Cited by 1,298
Social amnesia in mice lacking the oxytocin gene
Ferguson, J. N., Young, L. J., Hearn, E. F., Matzuk, M. M., Insel, T. R., & Winslow, J. T. (2000) · Nature Genetics · doi:10.1038/77040 · Cited by 1,130
Common genetic variants on 5p14.1 associate with autism spectrum disorders
Wang, K., Zhang, H., Ma, D., Bucan, M., Glessner, J. T., Abrahams, B. S., Salyakina, D., Imielinski, M., Bradfield, J. P., Sleiman, P. M. A., et al. (2009) · Nature · doi:10.1038/nature07999 · Cited by 989
Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders.
Guastella, A. J., Einfeld, S. L., Gray, K. M., Rinehart, N. J., Tonge, B. J., Lambert, T. J., & Hickie, I. B. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.09.020 · Cited by 962
Cited by
Sorted by citations
Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine
Meyer-Lindenberg, A., Domes, G., Kirsch, P., & Heinrichs, M. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3044 · Cited by 1,688
Oxytocin and social affiliation in humans
Feldman, R. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2012.01.008 · Cited by 767
Feldman, R., Gordon, I., Influs, M., Gutbir, T., & Ebstein, R. P. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.22 · Cited by 622
Psychological effects of breastfeeding on children and mothers
Krol, K. M., & Grossmann, T. (2018) · Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz · doi:10.1007/s00103-018-2769-0 · Cited by 407
Sensitive Parenting Is Associated with Plasma Oxytocin and Polymorphisms in the OXTR and CD38 Genes
Feldman, R., Zagoory-Sharon, O., Weisman, O., Schneiderman, I., Gordon, I., Maoz, R., Shalev, I., & Ebstein, R. P. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.12.025 · Cited by 393
Metadata
- Authors
- Munesue, T., Yokoyama, S., Nakamura, K., Anitha, A., Yamada, K., Hayashi, K., Asaka, T., Liu, H.-X., Jin, D., Koizumi, K., Islam, M. S., Huang, J.-J., Ma, W.-J., Kim, U.-H., Kim, S.-J., Park, K., Kim, D., Kikuchi, M., Ono, Y., Nakatani, H., Suda, S., Miyachi, T., Hirai, H., Salmina, A., Pichugina, Y. A., Soumarokov, A. A., Takei, N., Mori, N., Tsujii, M., Sugiyama, T., Yagi, K., Yamagishi, M., Sasaki, T., Yamasue, H., Kato, N., Hashimoto, R., Taniike, M., Hayashi, Y., Hamada, J., Suzuki, S., Ooi, A., Noda, M., Kamiyama, Y., Kido, M. A., Lopatina, O., Hashii, M., Amina, S., Malavasi, F., Huang, E. J., Zhang, J., Shimizu, N., Yoshikawa, T., Matsushima, A., Minabe, Y., & Higashida, H.
- Affiliations
- Kanazawa University (JP)
- Hamamatsu University (JP)
- RIKEN Center for Brain Science (JP)
- Nanao hospital (JP)
- Korea Advanced Institute of Science and Technology (KR)
- Corresponding author
- Higashida, Haruhiro
- ORCID
- Yokoyama, Shigeru
- Nakamura, Kazuhiko
- Anitha, Ayyappan
- Yamada, Kazuo
- Hayashi, Kenshi
- Kim, Uh-Hyun
- Park, Keunwan
- Kim, Dongsup
- Kikuchi, Mitsuru
- Ono, Yasuki
- Suda, Shiro
- Miyachi, Taishi
- Hirai, Hirokazu
- Salmina, Alla
- Tsujii, Masatsugu
- Sugiyama, Toshiro
- Yagi, Kunimasa
- Yamagishi, Masakazu
- Sasaki, Tsukasa
- Yamasue, Hidenori
- Hashimoto, Ryota
- Suzuki, Shioto
- Kido, Mizuho A.
- Lopatina, Olga
- Malavasi, Fabio
- Huang, Eric J.
- Zhang, Jiasheng
- Yoshikawa, Takeo
- Higashida, Haruhiro
- Venue
- Neuroscience Research
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 67
- Issue
- 2
- Pages
- 181-191
- ISSN
- 0168-0102 (ISSN-L)
- OpenAlex
- W2149724047
- Semantic Scholar
- add07ecbc7439e42eee6a7ccfffc8035b6731797
- Cited by
- 177
- References
- 59
- Citations by year
- 2026: 3 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 7 · 2020: 10 · 2019: 10 · 2018: 13 · 2017: 20 · 2016: 12 · 2015: 20 · 2014: 13 · 2013: 20 · 2012: 14
- FWCI
- 10.25
- Type
- journal article
- Language
- en
- Open access
- Locations
- Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Kanazawa University Repository for Academic Resources (DSpace) (Kanazawa University) (submittedVersion, cc-by-nc-nd)
- Funders
- San Francisco State University
- Fondazione Guido Berlucchi
- University of California, San Francisco
- Japan Society for the Promotion of Science (22590202, 21791118, 22590772)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Keywords
- CD38, autism spectrum disorder, oxytocin, single nucleotide polymorphisms, high-functioning autism, hypothalamus, social recognition, genetic association, plasma oxytocin, family trios, Japanese population
- MeSH terms
- Adolescent, Adult, Aged, Analysis of Variance, Brain, Child, Child Development Disorders, Pervasive, Child, Preschool, Cross-Cultural Comparison, Family Health, Female, Gene Frequency, Genotype, Humans, Immunoenzyme Techniques, Japan, Male, Middle Aged, Oxytocin, Vasopressins, Cohort Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, ADP-ribosyl Cyclase 1, Genome-Wide Association Study, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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