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.

Mother's warmth from maternal genes: genomic imprinting of brown adipose tissue.

Background and objectives: Brown adipose tissue (BAT) plays key roles in mammalian physiology, most notably with regard to thermoregulation in infants and juveniles. Previous studies have suggested that intragenomic conflict, in the form of genomic imprinting, mediates BAT thermogenesis, because it represents a public good for groups of siblings, or a mother with her offspring, who huddle together to conserve warmth. By this hypothesis, maternally expressed imprinted genes should promote BAT, while paternally expressed genes should repress it. Methodology: We systematically searched the literature using two curated lists of genes imprinted in humans and/or mice, in association with evidence regarding effects of perturbation to imprinted gene expression on BAT development or activity. Results: Overall, enhanced BAT was associated with relatively higher expression of maternally expressed imprinted genes, and relatively lower expression of paternally expressed imprinted genes; this pattern was found for 16 of the 19 genes with sufficient information for robust ascertainment (Binomial test, P < 0.005, 2-tailed). Conclusions and implications: These results support the kinship theory of imprinting and indicate that future studies of BAT, and its roles in human health and disease, may usefully focus on effects of imprinted genes and associated genomic conflicts.

Do the diverse phenotypes of Prader-Willi syndrome reflect extremes of covariation in typical populations?

The phenotypes of human imprinted neurogenetic disorders can be hypothesized as extreme alterations of typical human phenotypes. The imprinted neurogenetic disorder Prader-Willi syndrome (PWS) features covarying phenotypes that centrally involve altered social behaviors, attachment, mood, circadian rhythms, and eating habits, that can be traced to altered functioning of the hypothalamus. Here, we conducted analyses to investigate the extent to which the behavioral variation shown in typical human populations for a set of PWAS-associated traits including autism spectrum cognition, schizotypal cognition, mood, eating, and sleeping phenotypes shows covariability that recapitulates the covariation observed in individuals with PWS. To this end, we collected data from 296 typical individuals for this set of phenotypes, and showed, using principal components analysis, evidence of a major axis reflecting key covarying PWS traits. We also reviewed the literature regarding neurogenetic syndromes that overlap in their affected traits with PWS, to determine their prevalence and properties. These findings demonstrate that a notable suite of syndromes shows phenotypic overlap with PWS, implicating a large set of imprinted and non-imprinted genes, some of which interact, in the phenotypes of this disorder. Considered together, these findings link variation in and among neurogenetic disorders with variation in typical populations, especially with regard to pleiotropic effects mediated by the hypothalamus. This work also implicates effects of imprinted gene variation on cognition and behavior in typical human populations.

Does SNORD116 mediate aspects of psychosis in Prader-Willi syndrome? Evidence from a non-clinical population.

The paternally expressed gene SNORD116 encodes a set of short nucleolar RNAs that affect the expression of hundreds of other genes via epigenetic interactions. Lack of expression for SNORD116 has been implicated in major phenotypes of Prader-Willi Syndrome (PWS). Rates of psychosis and autism spectrum disorders are greatly increased in PWS, but the genetic and epigenetic causes of these increases remain unknown. We genotyped a large population of typical individuals for five SNPs within SNORD116 and phenotyped them for variation in schizotypal and autism spectrum traits. SNORD116 SNP and haplotype variation mediated variation exclusively in the Schizotypal Personality Questionnaire - Ideas of Reference subscale, which reflects variation in aspects of paranoia. The effect was restricted to females. SNORD116 represents, in addition to UBE3A and NDN-MAGEL2, a third, independent locus in the 15q11-q13 imprinted region that preferentially or exclusively affects levels of paranoia. This convergent pattern may reflect a common neural pathway affected by multiple genes, or an effect of interactions between the imprinted loci.

Genetic variation of UBE3A is associated with schizotypy in a population of typical individuals.

The maternally expressed imprinted gene UBE3A has been implicated in autism, schizophrenia and psychosis. The phenotype of Angelman syndrome, caused by loss of UBE3A expression, involves autism spectrum traits, while Prader-Willi syndrome, where the genotype of maternal disomy increases dosage of UBE3A, shows high penetrance for the development of psychosis. Maternal duplications of the 15q11-q13 chromosome region that overlap the imprinted region also show an association with schizophrenia, further implying a connection between increased dosage of UBE3A and the development of schizophrenia and psychosis. We phenotyped a large population of typical individuals for autism spectrum and schizotypal traits and genotyped them for a set of SNPs in UBE3A. Genetic variation of rs732739, an intronic SNP tagging a large haplotype spanning nearly the entire range of UBE3A, was significantly associated with variation in total schizotypy. Our results provide an independent line of evidence, connecting the imprinted UBE3A gene to the schizophrenia spectrum.

Baby food and bedtime: Evidence for opposite phenotypes from different genetic and epigenetic alterations in Prader-Willi and Angelman syndromes.

Prader-Willi and Angelman syndromes are often referred to as a sister pair of neurodevelopmental disorders, resulting from different genetic and epigenetic alterations to the same chromosomal region, 15q11-q13. Some of the primary phenotypes of the two syndromes have been suggested to be opposite to one another, but this hypothesis has yet to be tested comprehensively, and it remains unclear how opposite effects could be produced by changes to different genes in one syndrome compared to the other. We evaluated the evidence for opposite effects on sleep and eating phenotypes in Prader-Willi syndrome and Angelman syndrome, and developed physiological-genetic models that represent hypothesized causes of these differences. Sleep latency shows opposite deviations from controls in Prader-Willi and Angelman syndromes, with shorter latency in Prader-Willi syndrome by meta-analysis and longer latency in Angelman syndrome from previous studies. These differences can be accounted for by the effects of variable gene dosages of UBE3A and MAGEL2, interacting with clock genes, and leading to acceleration (in Prader-Willi syndrome) or deceleration (in Angelman syndrome) of circadian rhythms. Prader-Willi and Angelman syndromes also show evidence of opposite alterations in hyperphagic food selectivity, with more paternally biased subtypes of Angelman syndrome apparently involving increased preference for complementary foods ("baby foods"); hedonic reward from eating may also be increased in Angelman syndrome and decreased in Prader-Willi syndrome. These differences can be explained in part under a model whereby hyperphagia and food selectivity are mediated by the effects of the genes SNORD-116, UBE3A and MAGEL2, with outcomes depending upon the genotypic cause of Angelman syndrome. The diametric variation observed in sleep and eating phenotypes in Prader-Willi and Angelman syndromes is consistent with predictions from the kinship theory of imprinting, reflecting extremes of higher resource demand in Angelman syndrome and lower demand in Prader-Willi syndrome, with a special emphasis on social-attentional demands and attachment associated with bedtime, and feeding demands associated with mother-provided complementary foods compared to offspring-foraged family-type foods.