The structure of schizotypal personality traits: a cross-national study.

BACKGROUND: Schizotypal traits are considered a phenotypic-indicator of schizotypy, a latent personality organization reflecting a putative liability for psychosis. To date, no previous study has examined the comparability of factorial structures across samples originating from different countries and cultures. The main goal was to evaluate the factorial structure and reliability of the Schizotypal Personality Questionnaire (SPQ) scores by amalgamating data from studies conducted in 12 countries and across 21 sites. METHOD: The overall sample consisted of 27 001 participants (37.5% males, n = 4251 drawn from the general population). The mean age was 22.12 years (s.d. = 6.28, range 16-55 years). The SPQ was used. Confirmatory factor analysis (CFA) and Multilevel CFA (ML-CFA) were used to evaluate the factor structure underlying the SPQ scores. RESULTS: At the SPQ item level, the nine factor and second-order factor models showed adequate goodness-of-fit. At the SPQ subscale level, three- and four-factor models displayed better goodness-of-fit indices than other CFA models. ML-CFA showed that the intraclass correlation coefficients values were lower than 0.106. The three-factor model showed adequate goodness of fit indices in multilevel analysis. The ordinal α coefficients were high, ranging from 0.73 to 0.94 across individual samples, and from 0.84 to 0.91 for the combined sample. CONCLUSIONS: The results are consistent with the conceptual notion that schizotypal personality is a multifaceted construct and support the validity and utility of SPQ in cross-cultural research. We discuss theoretical and clinical implications of our results for diagnostic systems, psychosis models and cross-national mental health strategies.

Winter birth, urbanicity and immigrant status predict psychometric schizotypy dimensions in adolescents.

BACKGROUND: Urbanicity, immigration and winter-birth are stable epidemiological risk factors for schizophrenia, but their relationship to schizotypy is unknown. This is a first examination of the association of these epidemiological risk factors with positive schizotypy, in nonclinical adolescents, controlling for a range of potential and known confounders. METHODS: We collected socio-demographics, life-style, family and school circumstances, positive schizotypy dimensions and other personality traits from 445 high school pupils (192 males, 158 immigrants) from 9 municipalities in Athens and Heraklion, Greece, which covered a range of host population and migrant densities. Using multivariate hierarchical linear regressions models, we estimated the association of schizotypy dimensions with: (1) demographics of a priori interest (winter-birth, immigrant status, urban characteristics), including family financial and mental health status; (2) factors resulting from principal component analysis (PCA) of the demographic and personal data; (3) factors resulting from PCA of the personality questionnaires. RESULTS: Adolescent women scored higher on schizotypy than men. High anxiety/neuroticism was the most consistent and significant predictor of all schizotypy dimensions in both sexes. In the fully adjusted models, urbanicity predicted magical thinking and unusual experiences in women, while winter-birth and immigration predicted paranoid ideation and unusual experiences respectively in men. CONCLUSIONS: These results support the continuum hypothesis and offer potential insights in the nature of risk conferred by winter-birth, urbanicity and immigration and the nature of important sex differences. Controlling for a wide range of potential confounding factors increases the robustness of these results and confidence that these were not spurious associations.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

The effects of the CACNA1C rs1006737 A/G on affective startle modulation in healthy males.

BACKGROUND: The CACNA1C rs1006737 risk A allele has been associated with affective psychoses and functional studies indicate that it is associated with increased hippocampal/amygdala activity during emotional face-processing. Here we studied the impact of the risk A allele on affective startle modulation. METHODS: Hundred and ninety-four healthy males stratified for their CACNA1C rs1006737 genotype (GG:111, GA:67, AA:16) were presented with 18 pleasant, 18 unpleasant and 18 neutral pictures with acoustic probes (104 dB) occurring during 12 pictures in each affective category. Baseline startle was assessed during blank screens. State mood was self-rated on arrival, pre- and post-test and the emotional valence and arousal of affective pictures at post-test. RESULTS: Relative to the other genotypes, risk A allele homozygotes presented with higher anxiety/negative affect at pre-test, reduced and exaggerated physiological responses to the pleasant and negative pictures respectively, negative affect with reduced arousal at post-test and rated the affective pictures as less arousing and inconsistently to their physiological responses (all P<0.05). Sustained contextual negative mood predicted reduced baseline and affective startle reactivity in the AA group. CONCLUSIONS: Healthy homozygous males for the risk A allele appear to have marked contextual sensitivity, affective reactivity akin to anxiety and depression and inefficient emotional appraisal. Our findings provide phenotypic detail of the CACNA1C AA genotype in non-symptomatic individuals, which suggest primary effects in emotional circuitry, consistent with previously documented alterations in hippocampal/amygdala processing.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Sub-optimal parenting is associated with schizotypic and anxiety personality traits in adulthood.

Part of the variation in personality characteristics has been attributed to the child-parent interaction and sub-optimal parenting has been associated with psychiatric morbidity. In the present study, an extensive battery of personality scales (Trait Anxiety Inventory, Behavioural Inhibition/Activation System questionnaire, Eysenck Personality Questionnaire-Revised, Temperament and Character Inventory, Schizotypal Traits Questionnaire, Toronto Alexithymia Scale) and the Parental Bonding Instrument (PBI) were administered in 324 adult healthy males to elucidate the effects of parenting on personality configuration. Personality variables were analysed using Principal Component Analysis (PCA) and the factors "Schizotypy", "Anxiety", "Behavioural activation", "Novelty seeking" and "Reward dependence" were extracted. Associations between personality factors with PBI "care" and "overprotection" scores were examined with regression analyses. Subjects were divided into "parental style" groups and personality factors were subjected to categorical analyses. "Schizotypy" and "Anxiety" were significantly predicted by high maternal overprotection and low paternal care. In addition, the Affectionless control group (low care/high overprotection) had higher "Schizotypy" and "Anxiety" compared with the Optimal Parenting group (high care/low overprotection). These results further validate sub-optimal parenting as an important environmental exposure and extend our understanding on the mechanisms by which it increases risk for psychiatric morbidity.

Prepulse inhibition of the startle reflex depends on the catechol O-methyltransferase Val158Met gene polymorphism.

BACKGROUND: Recent evidence suggests that dopamine (DA) agonist-induced disruption of prepulse inhibition (PPI) depends on basal PPI values, in a manner that suggests an inverted U-shaped relationship between PPI and prefrontal DA levels. This is the first study to examine possible genetic determinants of PPI and the catechol O-methyltransferase (COMT) Val158Met polymorphism, the main catabolic pathway of released DA in the prefrontal cortex (PFC). METHOD: PPI was measured in 93 healthy males presented with 75-dB and 85-dB prepulses at 60-ms and 120-ms prepulse-pulse intervals. Subjects were grouped according to their COMT status into a Val/Val, a Val/Met and a Met/Met group. RESULTS: ANOVAs showed that at all prepulse and interval conditions, Val/Val individuals had the lowest PPI, Met/Met the highest, and Val/Met were intermediate. CONCLUSIONS: These results suggest that PPI is regulated by DA neurotransmission in the PFC and its levels depend on the COMT Val158Met gene polymorphism. These findings enhance the value of the PPI paradigm in examining individual variability of early information processing in healthy subjects and psychiatric disorders associated with changes in PFC DA activity and attentional deficits such as schizophrenia.

Differential effects of testosterone on protein synthesis activity in male and female quail brain.

In Japanese quail, testosterone (T) increases the Nissl staining density in the medial preoptic nucleus (POM) in relation to the differential activation by T of copulatory behavior. The effect of T on protein synthesis was quantified here in 97 discrete brain regions by the in vivo autoradiographic (14)C-leucine (Leu) incorporation method in adult gonadectomized male and female quail that had been treated for 4 weeks with T or left without hormone. T activated male sexual behaviors in males but not females. Overall Leu incorporation was increased by T in five brain regions, many of which contain sex steroid receptors such as the POM, archistriatum and lateral hypothalamus. T decreased Leu incorporation in the medial septum. Leu incorporation was higher in males than females in two nuclei but higher in females in three nuclei including the hypothalamic ventromedial nucleus. Significant interactions between effects of T and sex were seen in 13 nuclei: in most nuclei (n=12), T increased Leu incorporation in males but decreased it in females. The POM boundaries were defined by a denser Leu incorporation than the surrounding area and incorporation was increased by T more in males (25%) than in females (6%). These results confirm that protein synthesis in brain areas relevant to the control of sexual behavior can be affected by the sex of the subjects or their endocrine condition and that T can have differential effects in the two sexes. These anabolic changes should reflect the sexually differentiated neurochemical mechanisms mediating behavioral activation.