Genetic evidence of gender difference in autism spectrum disorder supports the female-protective effect

Zhang, Yi; Li, Na; Li, Chao; Zhang, Ze; Teng, Huajing; Wang, Yan; Zhao, Tingting; Shi, Leisheng; Zhang, Kun; Xia, Kun; Li, Jinchen; Sun, Zhen

doi:10.1038/s41398-020-0699-8

Cited by 118 publications

(75 citation statements)

References 78 publications

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“…The current male-bias in ASD raises the question of how sex prevalence might be relevant to the underlying mechanisms of this disorder. There are many possible explanations ranging from the differences in the mechanisms involved in males and females to the presence of protective mechanisms in the latter or vulnerability mechanisms in the former (Halladay et al, 2015;Lai et al, 2015;Ferri et al, 2018;Zhang et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Auditory Processing Differences Correlate With Autistic Traits in Males

Aykan

Gürses

Tokgöz-Yılmaz

et al. 2020

Front. Hum. Neurosci.

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Autism spectrum disorder (ASD) has high prevalence among males compared to females but mechanisms underlying the differences between sexes are poorly investigated. Moreover, autistic symptoms show a continuity in the general population and are referred to as autistic traits in people without an ASD diagnosis. One of the symptoms of ASD is sensory processing differences both in sensitivity and perception. To investigate sensory processing differences in autistic traits, we examined auditory and visual processing in a healthy population. We recruited 75 individuals (39 females and 36 males, mean age = 23.01 years, SD = 3.23 years) and assessed autistic traits using the Autism Spectrum Quotient, and sensory sensitivity using the Sensory Sensitivity Scales. Sensory processing in the visual domain was examined with the radial motion stimulus and the auditory domain was assessed with the 1,000 Hz pure tone stimulus with electroencephalography-evoked potentials. The results showed that the auditory sensitivity scores of the males (r aud (34) = 0.396, p aud = 0.017) and the visual sensitivity scores of females were correlated with autistic traits (r vis (37) = 0.420, p vis = 0.008). Moreover, the P2 latency for the auditory stimulus was prolonged in the participants with a higher level of autistic traits (r s (61) = 0.411, p = 0.008), and this correlation was only observed in males (r s (31) = 0.542, p = 0.001). We propose that auditory processing differences are related to autistic traits in neurotypicals, particularly in males. Our findings emphasize the importance of considering sex differences in autistic traits and ASD.

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Section: Introductionmentioning

confidence: 99%

Auditory Processing Differences Correlate With Autistic Traits in Males

Aykan

Gürses

Tokgöz-Yılmaz

et al. 2020

Front. Hum. Neurosci.

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“…Regarding ASD-related genes, we found Nlgn3 mRNA expression was significantly decreased in DE-SOA-exposed male rats, but not in the female rats in the present study. A recent report has indicated that developmental exposure to PM 2.5 caused autism-like behaviors, such as poor social interaction and repetitive behavior, accompanied by lower oxytocin receptor (OXTR) protein level, catalase activity, and glutathione (GSH) concentration, in 7-week-old male rats [ 59 ]. Different hormonal milieu, receptor type and function, and maturation of neural network may contribute the sex-specific effects in ASD.…”

Section: Discussionmentioning

confidence: 99%

Perinatal Exposure to Diesel Exhaust-Origin Secondary Organic Aerosol Induces Autism-Like Behavior in Rats

Win-Shwe

Kyi-Tha-Thu

Fujitani

et al. 2021

IJMS

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication, poor social interactions, and repetitive behaviors. We aimed to examine autism-like behaviors and related gene expressions in rats exposed to diesel exhaust (DE)-origin secondary organic aerosol (DE-SOA) perinatally. Sprague–Dawley pregnant rats were exposed to clean air (control), DE, and DE-SOA in the exposure chamber from gestational day 14 to postnatal day 21. Behavioral phenotypes of ASD were investigated in 10~13-week-old offspring using a three-chambered social behavior test, social dominance tube test, and marble burying test. Prefrontal cortex was collected to examine molecular analyses including neurological and immunological markers and glutamate concentration, using RT-PCR and ELISA methods. DE-SOA-exposed male and female rats showed poor sociability and social novelty preference, socially dominant behavior, and increased repetitive behavior. Serotonin receptor (5-HT(5B)) and brain-derived neurotrophic factor (BDNF) mRNAs were downregulated whereas interleukin 1 β (IL-β) and heme oxygenase 1 (HO-1) mRNAs were upregulated in the prefrontal cortex of male and female rats exposed to DE-SOA. Glutamate concentration was also increased significantly in DE-SOA-exposed male and female rats. Our results indicate that perinatal exposure to DE-SOA may induce autism-like behavior by modulating molecules such as neurological and immunological markers in rats.

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“…However, ascertainment bias for the neurodevelopmental phenotype could also contribute to the male predominance. Nevertheless, it is tempting to speculate that sex-linked traits could affect susceptibility to clinical penetrance and spectrum of SETD1B variants, as female-protective effects have been proposed for other neurodevelopmental disorders 32,33 .…”

Section: Discussionmentioning

confidence: 99%

Delineating the molecular and phenotypic spectrum of theSETD1B-related syndrome

Weerts¹,

Lanko²,

Guzmán‐Vega³

et al. 2021

Preprint

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Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay and seizures. To date, clinical features have been described for eleven patients with (likely) pathogenic SETD1B sequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Interestingly, males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Finally, despite the possibility of non-redundant contributions of SETD1B and its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

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Genetic evidence of gender difference in autism spectrum disorder supports the female-protective effect

Cited by 118 publications

References 78 publications

Auditory Processing Differences Correlate With Autistic Traits in Males

Auditory Processing Differences Correlate With Autistic Traits in Males

Perinatal Exposure to Diesel Exhaust-Origin Secondary Organic Aerosol Induces Autism-Like Behavior in Rats

Delineating the molecular and phenotypic spectrum of theSETD1B-related syndrome

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