Silven Read

The PCSK6 gene is associated with handedness, the autism spectrum, and magical ideation in a non-clinical population

Common polymorphisms in the gene PCSK6, whose protein product mediates the development of brain and body asymmetry through the NODAL pathway, have recently been associated with handedness in three studies, making it a key candidate gene for understanding the developmental and expression of human lateralization. We tested the hypothesis that the PCSK6 VNTR polymorphism rs1053972 influences the expression of handedness and aspects of dimensional schizotypy and autism. For a sample of 709 healthy individuals, rs1053972 genotype was significantly associated with categorical measures of handedness, and with dimensional handedness in subsets of the population with high schizotypy and magical ideation or a lack of strong right-handedness. Both findings showed evidence of stronger or exclusive effects among females, compared to males. Genotypes of PCSK6 also showed significant sex-limited associations with magical ideation, a component of positive schizotypal cognition measured using the Schizotypal Personality Questionnaire, and total autism score, measured using the Autism Spectrum Quotient. These results partially replicate previous studies on effects of PCSK6 rs1053972 genetic variation on handedness phenotypes, link the PCSK6 gene with the dimensional expression of neurodevelopmental conditions in healthy individuals, and show that associations of this gene with handedness and psychological phenotypes exhibit evidence of sex-limited effects.

A genetic locus for paranoia

The psychological effects of brain-expressed imprinted genes in humans are virtually unknown. Prader–Willi syndrome (PWS) is a neurogenetic condition mediated by genomic imprinting, which involves high rates of psychosis characterized by hallucinations and paranoia, as well as autism. Altered expression of two brain-expressed imprinted genes, MAGEL2 and NDN, mediates a suite of PWS-related phenotypes, including behaviour, in mice. We phenotyped a large population of typical individuals for schizophrenia-spectrum and autism-spectrum traits, and genotyped them for the single-nucleotide polymorphism rs850807, which is putatively functional and linked with MAGEL2 and NDN. Genetic variation in rs850807 was strongly and exclusively associated with the ideas of reference subscale of the schizophrenia spectrum, which is best typified as paranoia. These findings provide a single-locus genetic model for analysing the neurological and psychological bases of paranoid thinking, and implicate imprinted genes, and genomic conflicts, in human mentalistic thought.

The Williams syndrome prosociality gene GTF2I mediates oxytocin reactivity and social anxiety in a healthy population

The neurohormone oxytocin plays a central role in human social behaviour and cognition, and oxytocin dysregulation may contribute to psychiatric disorders. However, genetic factors influencing individual variation in the oxytocinergic system remain poorly understood. We genotyped 169 healthy adults for a functional polymorphism in GTF2I (general transcription factor II-I), a gene associated with high prosociality and reduced social anxiety in Williams syndrome, a condition reported to involve high oxytocin levels and reactivity. Participants’ salivary oxytocin levels were measured before and after watching a validated empathy-inducing video. Oxytocin reactivity, defined as pre- to post-video percentage change in salivary oxytocin, varied substantially and significantly between individuals with different GTF2I genotypes, with, additionally, a trend towards an interaction between genotype and sex. Individuals with more oxytocin-reactive genotypes also reported significantly lower social anxiety. These findings suggest a model whereby GTF2I has a continuum of effects on human sociality, from the extreme social phenotypes and oxytocin dysregulation associated with gene deletion in Williams syndrome, to individual differences in oxytocin reactivity and sociality associated with common polymorphisms in healthy populations.

Inhibition of NF-κB-dependent HIV-1 replication by the marine natural product bengamide A

ABSTRACT HIV‐1 inhibitors that act by mechanisms distinct from existing antiretrovirals can provide novel insights into viral replication and potentially inform development of new therapeutics. Using a multi‐cycle HIV‐1 replication assay, we screened 252 pure compounds derived from marine invertebrates and microorganisms and identified 6 (actinomycin Z2, bastadin 6, bengamide A, haliclonacyclamine A + B, keramamine C, neopetrosiamide B) that inhibited HIV‐1 with 50% effective concentrations (EC50s) of 3.8 &mgr;M or less. The most potent inhibitor, bengamide A, blocked HIV‐1 in a T cell line with an EC50 of 0.015 &mgr;M and in peripheral blood mononuclear cells with an EC50 of 0.032 &mgr;M. Bengamide A was previously described to inhibit NF‐&kgr;B signaling. Consistent with this mechanism, bengamide A suppressed reporter expression from an NF‐&kgr;B‐driven minimal promoter and an HIV‐1 long terminal repeat (LTR) with conserved NF‐&kgr;B response elements, but lacked activity against an LTR construct with mutation of these elements. In single‐cycle HIV‐1 infection assays, bengamide A also suppressed viral protein expression when viruses encoded an intact LTR but exhibited minimal activity against those with mutated NF‐&kgr;B elements. Finally, bengamide A did not inhibit viral DNA accumulation, indicating that it likely acts downstream of this step in HIV‐1 replication. Our study identifies multiple new antiviral compounds including an unusually potent inhibitor of HIV‐1 gene expression. Graphical abstract Figure. No caption available. Highlights6 novel HIV‐1 inhibitors were identified from a pure marine natural products library.The most active compound, bengamide A, inhibits HIV‐1 in cell lines and primary cells with sub‐micromolar efficacy.The HIV‐1 LTR NF‐&kgr;B response elements are required for Bengamide A‐mediated inhibition of LTR‐dependent gene expression.An HIV‐1 strain with mutated LTR NF‐kB sites exhibits in vitro resistance to bengamide A.

Segregating polymorphism in the NMDA receptor gene GRIN2A , schizotypy, and mental rotation among healthy individuals

ABSTRACT Common alleles associated with psychiatric disorders are often regarded as deleterious genes that influence vulnerability to disease, but they may also be considered as mediators of variation in adaptively structured cognitive phenotypes among healthy individuals. The schizophrenia‐associated gene GRIN2A (glutamate ionotropic receptor NMDA type subunit 2a) codes for a protein subunit of the NMDA (N‐methyl‐D‐aspartate) receptor that underlies central aspects of human cognition. Pharmacological NMDA blockage recapitulates the major features of schizophrenia in human subjects, and represents a key model for the neurological basis of this disorder. We genotyped two functional GRIN2A polymorphisms in a large population of healthy individuals who were scored for schizotypy and mental imagery/manipulation (the mental rotation test). Rare‐allele homozygosity of the promoter microsatellite rs3219790 was associated with high total schizotypy (after adjustment for multiple comparisons) and with enhanced mental rotation ability (nominally, but not after adjustment for multiple comparisons), among males. These findings provide preliminary evidence regarding a genetic basis to previous reports of enhanced mental imagery in schizophrenia and schizotypy. The results also suggest that some schizophrenia‐related alleles may be subject to cognitive tradeoffs involving both positive and negative effects on psychological phenotypes, which may help to explain the maintenance of psychiatric‐disorder risk alleles in human populations. HighlightsSchizophrenia and schizotypy involve enhanced mental imagery.GRIN2A genotypes are nominally associated with mental rotation and schizotypy.High schizotypy may confer mental imagery benefits in healthy populations.

The SETDB2 locus: evidence for a genetic link between handedness and atopic disease

The gene SETDB2, which mediates aspects of laterality in animal model systems, has recently been linked with human handedness as measured continuously on a scale from strong left to strong right. By contrast, it was marginally associated with a left-right dichotomous measure, and it showed no evidence of association with absolute handedness strength independent of direction. We genotyped the SETDB2 handedness-associated single nucleotide polymorphism, rs4942830, in a large healthy population likewise phenotyped for continuous, absolute, and dichotomous handedness variables. Our results demonstrated significant effects of rs4942830 genotype on continuous handedness, and weaker, marginal effects on dichotomous handedness, but no effects on absolute handedness. These results help to establish the locus marked by the SNP rs4942830 as a strong candidate for mediating human handedness. Intriguingly, rs4942830 is also in complete linkage disequilibrium with rs386770867, a polymorphism recently shown to affect human serum levels of IgE production and other atopic phenotypes. These findings implicate this locus in the longstanding links of handedness with asthma and other atopic diseases.

Supplementary material from "The Williams syndrome prosociality gene GTF2I mediates oxytocin reactivity and social anxiety in a healthy population"

The neurohormone oxytocin plays a central role in human social behaviour and cognition, and oxytocin dysregulation may contribute to psychiatric disorders. However, genetic factors influencing individual variation in the oxytocinergic system remain poorly understood. We genotyped 169 healthy adults for a functional polymorphism in GTF2I ( general transcription factor II-I ), a gene associated with high prosociality and reduced social anxiety in Williams syndrome, a condition reported to involve high oxytocin levels and reactivity. Participants’ salivary oxytocin levels were measured before and after watching a validated empathy-inducing video. Oxytocin reactivity, defined as pre- to post-video percentage change in salivary oxytocin, varied substantially and significantly between individuals with different GTF2I genotypes, with, additionally, a trend towards an interaction between genotype and sex. Individuals with more oxytocin-reactive genotypes also reported significantly lower social anxiety. These findings suggest a model whereby GTF2I has a continuum of effects on human sociality, from the extreme social phenotypes and oxytocin dysregulation associated with gene deletion in Williams syndrome, to individual differences in oxytocin reactivity and sociality associated with common polymorphisms in healthy populations.