Association between ASMT and autistic-like traits in children from a Swedish nationwide cohort

Persons with autism spectrum disorders (ASDs) often display low levels of melatonin, and it has been suggested that this decrease may be due to low activity of the acetylserotonin O-methyltransferase (ASMT), the last enzyme in the melatonin synthesis pathway. Moreover, genetic variants in ASMT have been associated with autism, as well as with low ASMT activity and melatonin levels, suggesting that the low ASMT activity observed in autism may partly be due to variation within the ASMT gene. In this study, we present a symptom-based approach to investigate possible associations between ASMT and autistic-like traits (ALTs) in the general population. To this end, continuous measures of ALTs were assessed in a nationally representative twin cohort (n=1771) from Sweden and six Single Nucleotide Polymorphisms (SNP) and a duplication of exon 2 to 8 in ASMT were genotyped. Our results show a nominally significant association, in girls, between one SNP (rs5949028) in the last intron of ASMT and social interaction impairments. No significant association, however, was observed with traits related to language impairment or restricted and repetitive behavior. In conclusion, our results support the possible involvement of the ASMT gene in ASDs and our finding that only one of three traits shows association suggests that genetic research may benefit from taking a symptom-specific approach to identify genes involved in autism psychopathology.VetenskapsrådetAccepte

The observed association between maternal anxiety and adolescent asthma : children of twin design suggest familial effects

BACKGROUND: Previous studies indicate that maternal anxiety is associated with asthma in the adolescent child, but mechanisms are unclear. OBJECTIVE: To investigate the association between maternal anxiety and maternal, self- and register-based report of asthma in the adolescent child, and whether the association remains after control of familial confounding (shared environmental and genetic factors). METHOD: From the Twin and Offspring Study of Sweden, 1691 mothers (1058 twins) and their adolescent child were included. The association between maternal self-reported anxiety (Beck Anxiety Inventory (BAI) and Karolinska Scales of Personality (KSP) somatic or psychic anxiety) and asthma based on subjective (maternal or child report) or objective (register-based diagnosis and medication) measures were analysed using logistic regression. The children-of-twins design was used to explore whether genes or environment contribute to the association. RESULTS: Maternal BAI anxiety (OR 2.02, CI 1.15-3.55) was significantly associated with adolescent asthma reported by the mother. Maternal KSP somatic anxiety (OR 1.74, CI 1.04-2.91) and psychic anxiety (OR 1.74, CI 1.05-2.86) was significantly associated with breathlessness reported by the adolescent child. In contrast, maternal anxiety was not associated with increased risk for the register-based outcomes of asthma diagnosis or medication. The results remained also after adjusting for covariates and the children-of-twins analyses which indicate that the association was due to familial confounding. CONCLUSIONS: We found some associations between maternal anxiety and subjectively reported offspring asthma or breathlessness which may be due to familial effects. A likely candidate for explaining this familial confounding is heritable personality traits associated with both anxiety and subjective measures of asthma.NonePublishe

Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo

Long-lasting, latently infected resting CD4+ T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir1. Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect2–9. Here we show that activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow–liver–thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4+ T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal—in combination with appropriate tools for systemic clearance of persistent HIV infection—greatly increases opportunities for HIV eradication

Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells

Human immunodeficiency virus (HIV) persists indefinitely in individuals with HIV who receive antiretroviral therapy (ART) owing to a reservoir of latently infected cells that contain replication-competent virus1–4. Here, to better understand the mechanisms responsible for latency persistence and reversal, we used the interleukin-15 superagonist N-803 in conjunction with the depletion of CD8+ lymphocytes in ART-treated macaques infected with simian immunodeficiency virus (SIV). Although N-803 alone did not reactivate virus production, its administration after the depletion of CD8+ lymphocytes in conjunction with ART treatment induced robust and persistent reactivation of the virus in vivo. We found viraemia of more than 60 copies per ml in all macaques (n = 14; 100%) and in 41 out of a total of 56 samples (73.2%) that were collected each week after N-803 administration. Notably, concordant results were obtained in ART-treated HIV-infected humanized mice. In addition, we observed that co-culture with CD8+ T cells blocked the in vitro latency-reversing effect of N-803 on primary human CD4+ T cells that were latently infected with HIV. These results advance our understanding of the mechanisms responsible for latency reversal and lentivirus reactivation during ART-suppressed infection

No genetic contribution to variation in human offspring sex ratio: a total population study of 4.7 million births

The ratio of males to females among an individual's offspring at birth (offspring sex ratio) has long been of great interest to evolutionary biologists. The human offspring sex ratio is around 1 : 1 and is understood primarily in terms of Fisher's principle (R. A. Fisher, , 1930), which is based on the insight that in a population with an unequal sex ratio, each individual of the rarer sex will on average have greater reproductive value than each individual of the more common sex. Accordingly, individuals genetically predisposed to produce the rarer sex will tend to have greater fitness and thus genes predisposing to bearing that sex will increase in frequency until the population sex ratio approaches 1 : 1. An assumption of this perspective is that individuals' offspring sex ratio is heritable. However, the heritability in humans remains remarkably uncertain, with inconsistent findings and important power limitations of existing studies. To address this persistent uncertainty, we used data from the entire Swedish-born population born 1932 or later, including 3 543 243 individuals and their 4 753 269 children. To investigate whether offspring sex ratio is influenced by genetic variation, we tested the association between individuals' offspring's sex and their siblings' offspring's sex ( pairs = 14 015 421). We estimated that the heritability for offspring sex ratio was zero, with an upper 95% confidence interval of 0.002, rendering Fisher's principle and several other existing hypotheses untenable as frameworks for understanding human offspring sex ratio

No genetic contribution to variation in human offspring sex ratio: a total population study of 4.7 million births

The ratio of males to females among an individual's offspring at birth (offspring sex ratio) has long been of great interest to evolutionary biologists. The human offspring sex ratio is around 1 : 1 and is understood primarily in terms of Fisher's principle (R. A. Fisher, The genetical theory of natural selection, 1930), which is based on the insight that in a population with an unequal sex ratio, each individual of the rarer sex will on average have greater reproductive value than each individual of the more common sex. Accordingly, individuals genetically predisposed to produce the rarer sex will tend to have greater fitness and thus genes predisposing to bearing that sex will increase in frequency until the population sex ratio approaches 1 : 1. An assumption of this perspective is that individuals' offspring sex ratio is heritable. However, the heritability in humans remains remarkably uncertain, with inconsistent findings and important power limitations of existing studies. To address this persistent uncertainty, we used data from the entire Swedish-born population born 1932 or later, including 3 543 243 individuals and their 4 753 269 children. To investigate whether offspring sex ratio is influenced by genetic variation, we tested the association between individuals' offspring's sex and their siblings' offspring's sex (n pairs = 14 015 421). We estimated that the heritability for offspring sex ratio was zero, with an upper 95% confidence interval of 0.002, rendering Fisher's principle and several other existing hypotheses untenable as frameworks for understanding human offspring sex ratio

The Macaque Social Responsiveness Scale (mSRS): A Rapid Screening Tool for Assessing Variability in the Social Responsiveness of Rhesus Monkeys (Macaca mulatta).

Understanding the biological mechanisms underlying human neuropsychiatric disorders, such as autism spectrum disorder (ASD), has been hindered by the lack of a robust, translational animal model. Rhesus monkeys (Macaca mulatta) display many of the same social behaviors that are affected in ASD, making them an excellent animal species in which to model social impairments. However, the social impairments associated with ASD may reflect extreme ends of a continuous distribution of traits. Thus, to validate the rhesus monkey as an animal model for studying social impairments that has strong translational relevance for ASD, researchers need an easily-implemented measurement tool that can quantify variation in social behavior dimensionally. The Social Responsiveness Scale (SRS) is a 65-item survey that identifies both typical and atypical social behaviors in humans that covary with ASD symptom severity. A chimpanzee SRS has already been validated and the current study adapted this tool for use in the rhesus monkey (mSRS). Fifteen raters completed the mSRS for 105 rhesus monkeys living at the Yerkes National Primate Research Center. The mSRS scores showed a unimodal distribution with a positive skew that identified 6 statistical outliers. Inter-rater reliability was very strong, but only 17 of the 36 questions showed positive intra-item reliability. The results of an exploratory factor analysis identified 3 factors that explained over 60% of the variance, with 12 items significantly loading onto the primary factor. These items reflected behaviors associated with social avoidance, social anxiety or inflexibility and social confidence. These initial findings are encouraging and suggest that variability in the social responsiveness of rhesus monkeys can be quantified using the mSRS: a tool that has strong translational relevance for human disorders. With further modification, the mSRS may provide an promising new direction for research on the biological mechanisms underlying social impairments

Heritability of the human connectome: A connectotyping study

Recent progress in resting-state neuroimaging demonstrates that the brain exhibits highly individualized patterns of functional connectivity—a “connectotype.” How these individualized patterns may be constrained by environment and genetics is unknown. Here we ask whether the connectotype is familial and heritable. Using a novel approach to estimate familiality via a machine-learning framework, we analyzed resting-state fMRI scans from two well-characterized samples of child and adult siblings. First we show that individual connectotypes were reliably identified even several years after the initial scanning timepoint. Familial relationships between participants, such as siblings versus those who are unrelated, were also accurately characterized. The connectotype demonstrated substantial heritability driven by high-order systems including the fronto-parietal, dorsal attention, ventral attention, cingulo-opercular, and default systems. This work suggests that shared genetics and environment contribute toward producing complex, individualized patterns of distributed brain activity, rather than constraining local aspects of function. These insights offer new strategies for characterizing individual aberrations in brain function and evaluating heritability of brain networks. By using machine learning and two independent datasets, this report shows that the brain’s individualized functional connectome or connectotype is familial and heritable. First we expand previous findings showing that by using a model-based approach to characterize functional connectivity, we can reliably identify and track individual brain signatures—a functional “fingerprint” or “connectotype” for the human brain—in both children and adults. Such signatures can also be used to characterize familial and heritable patterns of brain connectivity, even using limited data. Most heritable systems include the fronto-parietal, dorsal attention, ventral attention, cingulo-opercular, and default systems. Our proposed approach offers new strategies for characterizing normative development as well as altered patterns of brain connectivity and assists in characterizing the associations between genetic and epigenetic factors with brain function