Cold executive function processes and their hot analogs in schizotypy.

OBJECTIVE: To examine cold (based on logical reasoning) versus hot (having emotional components) executive function processes in groups with high individual schizotypal traits. METHOD: Two-hundred and forty-seven participants were administered the Schizotypal Personality Questionnaire and were allocated into schizotypal (cognitive-perceptual, paranoid, negative, disorganized) or control groups according to pre-specified criteria. Participants were also administered a battery of tasks examining working memory, complex selective attention, response inhibition, decision-making and fluid intelligence and their affective counterparts. The outcome measures of each task were reduced to one composite variable thus formulating five cold and five hot cognitive domains. Between-group differences in the cognitive domains were examined with repeated measures analyses of covariance. RESULTS: For working memory, the control and the cognitive-perceptual groups outperformed negative schizotypes, while for affective working memory controls outperformed the disorganized group. Controls also scored higher compared with the disorganized group in complex selective attention, while both the control and the cognitive-perceptual groups outperformed negative schizotypes in complex affective selective attention. Negative schizotypes also had striking difficulties in response inhibition, as they scored lower compared with all other groups. Despite the lack of differences in fluid intelligence, controls scored higher compared with all schizotypal groups (except from cognitive-perceptual schizotypes) in emotional intelligence; the latter group reported higher emotional intelligence compared with negative schizotypes. CONCLUSION: Results indicate that there is no categorical association between the different schizotypal dimensions with solely cold or hot executive function processes and support impoverished emotional intelligence as a core feature of schizotypy.

Maternal sleep disturbances during late pregnancy and child neuropsychological and behavioral development in early childhood.

The present study aims to explore the association of maternal sleep disturbances during late pregnancy on child neuropsychological and behavioral development in preschool years. The study included 638 mother-child pairs from the prospective Rhea mother-child cohort in Crete, Greece. Information on antenatal sleep disturbances was collected through a computer-assisted interview. Children's neuropsychological and behavioral development was assessed using the McCarthy Scales of Children's Abilities (MSCA), the Attention-Deficit Hyperactivity Disorder Test (ADHDT), and the Strengths and Difficulties Questionnaire (SDQ). Multivariate analysis showed that maternal sleep duration less than 8 h was associated with reduced scores in the general cognitive scale (ß = -2.28, 95% CI -4.54, -0.02, R2 = 0.417) and memory span (ß = -3.24, 95% CI -5.72, -0.77, R2 = 0.304), while mild-severe daytime sleepiness was associated with reduced scores in the memory scale (ß = -5.42, 95% CI -10.47, -0.37, R2 = 0.304), memory span (ß = -5.44, 95% CI -10.68, -0.21, R2 = 0.304), nd functions of posterior cortex (ß = -5.55, 95% CI -10.40, -0.70, R2 = 0.393) of MSCA. Snoring in late pregnancy was related to higher child hyperactivity scores in SDQ (ß = 1.05, 95% CI 0.16, 1.95, R2 = 0.160). An interaction between child sex and maternal sleep duration in response to ADHD symptoms was also found (p for interaction < 0.05). Stratified analysis revealed increased hyperactivity, inattention, and ADHD total scores for girls of mothers with sleep duration less than 8 h. Maternal sleep disturbances during pregnancy may be associated with impaired child neuropsychological and behavioral development during the preschool years. Early detection and intervention is necessary to reduce sleep disturbances habits in pregnancy and improve child neurodevelopment.

The association of schizotypal traits with Prepulse Inhibition: a double approach exploration.

Introduction: According to the fully-dimensional approach, schizotypy is a personality trait present in the population in a continuous manner while the quasi-dimensional approach emphasises its extreme presentations. In this study we examined the relationship between sensorimotor gating, a core risk-index of the schizophrenia-spectrum, and four schizotypal factors in a dimensional-wise and a dichotomising-wise approach. Methods: Two-hundred and eighty-three participants were assessed with the Schizotypal Personality Questionnaire and were tested for Prepulse Inhibition (PPI). Associations between the schizotypal factors and startle measures were examined with stepwise regressions (dimensional-wise approach). Individuals in the lower 20% or the upper 20% for each schizotypal factor were identified and between-group comparisons were conducted (dichotomising-wise approach). Results: We found that with both approaches, only high paranoid or negative schizotypy were associated with reduced PPI. The low negative schizotypy group had prolonged onset and peak latencies, indicating that prolonged stimulus detection accompanies superior sensorimotor gating in this group. Conclusions: The findings suggest that although differentiating the effects of the various schizotypal factors is primary, the approach employed is secondary. The study also adds evidence in the literature supporting PPI as a useful endophenotypic marker of the schizophrenia-spectrum and highlights the contribution of specific aspects of schizotypy.

Association between high levels of inflammatory markers and cognitive outcomes at 4 years of age: The Rhea mother-child cohort study, Crete, Greece.

There is growing evidence associating inflammatory markers in complex, higher order neurological functions, such as cognition and memory. We examined whether high levels of various inflammatory markers are associated with cognitive outcomes at 4 years of age in a mother-child cohort in Crete, Greece (Rhea study). We included 642 children in this cross-sectional study. Levels of several inflammatory markers (IFN-γ, IL-1ß, IL-6, IL-8, IL-17α, IL-10, MIP-1α, TNF-α and the ratios of IL-6 to IL-10 and TNF-α to IL-10) were determined in child serum via immunoassay. Neurodevelopment at 4 years was assessed by means of the McCarthy Scales of Children's Abilities. Multivariate linear regression analyses were used to estimate the associations between the exposures and outcomes of interest after adjustment for various confounders. Our results indicate that children with high TNF-α concentrations (≥90th percentile) in serum demonstrated decreased scores in memory (adjusted ß = -4.0; 95% CI: -7.7, -0.2), working memory (adjusted ß = -4.0; 95% CI: -8.0, -0.1) as well as in memory span scale (adjusted ß = -4.0; 95% CI: -7.9, -0.1). We also found that children with high IFN-γ serum levels showed lower scores in memory span scale (adjusted ß = -3.4; 95% CI: -7.3, -0.4). Children with elevated TNF-α/IL-10 ratio demonstrated decreased quantitative (adjusted ß = -4.3; 95% CI: -8.2, -0.4), motor (adjusted ß = -3.5; 95% CI: -7.5, -0.5), executive function (adjusted ß = -4.8; 95% CI: -8.5, -1.1), general cognitive (adjusted ß = -3.6; 95% CI: -7.3, -0.1), memory (adjusted ß = -3.8; 95% CI: -7.6, -0), working memory (adjusted ß = -3.5; 95% CI: -7.5, -0.5) and memory span scores (adjusted ß = -5.3; 95% CI: -9.1, -1.4) The findings suggest that high levels of TNF-α may contribute to reduced memory performance at preschool age.

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Meta-analysis on the association between genetic polymorphisms and prepulse inhibition of the acoustic startle response.

Sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) has been proposed as one of the most promising electrophysiological endophenotypes of schizophrenia. During the past decade, a number of publications have reported significant associations between genetic polymorphisms and PPI in samples of schizophrenia patients and healthy volunteers. However, an overall evaluation of the robustness of these results has not been published so far. Therefore, we performed the first meta-analysis of published and unpublished associations between gene polymorphisms and PPI of ASR. Unpublished associations between genetic polymorphisms and PPI were derived from three independent samples. In total, 120 single observations from 16 independent samples with 2660 study participants and 43 polymorphisms were included. After correction for multiple testing based on false discovery rate and considering the number of analyzed polymorphisms, significant associations were shown for four variants, even though none of these associations survived a genome-wide correction (P<5∗10-8). These results imply that PPI might be modulated by four genotypes - COMT rs4680 (primarily in males), GRIK3 rs1027599, TCF4 rs9960767, and PRODH rs385440 - indicating a role of these gene variations in the development of early information processing deficits in schizophrenia. However, the overall impact of single genes on PPI is still rather small suggesting that PPI is - like the disease phenotype - highly polygenic. Future genome-wide analyses studies with large sample sizes will enhance our understanding on the genetic architecture of PPI.

Stress-Dependent Association Between Polygenic Risk for Schizophrenia and Schizotypal Traits in Young Army Recruits.

Schizotypal personality traits may increase proneness to psychosis and likely index familial vulnerability to schizophrenia (SZ), implying shared genetic determinants with SZ. Here, we sought to investigate the contribution of common genetic risk variation for SZ on self-reported schizotypy in 2 ethnically homogeneous cohorts of healthy young males during compulsory military service, enrolled in the Athens Study of Proneness and Incidence of Schizophrenia (ASPIS, N = 875) and the Learning on Genetics of Schizophrenia Spectrum study (LOGOS, N = 690). A follow-up psychometric assessment was performed in a sub-sample of the ASPIS (N = 121), 18 months later at military service completion. Polygenic risk scores (PRS) for SZ were derived based on genome-wide association meta-analysis results from the Psychiatric Genomics Consortium. In the ASPIS, higher PRSSZ significantly associated with lower levels of positive (ie, perceptual distortions), disorganization and paranoid facets of schizotypy, whereas no association with negative (ie, interpersonal) facets was noted. Importantly, longitudinal data analysis in the ASPIS subsample revealed that PRSSZ was inversely associated with positive schizotypy at military induction (stressed condition) but not at follow-up (nonstressed condition), providing evidence for environmental rather than SZ-implicated genetic influences. Moreover, consistent with prior reports, PRSSZ was positively correlated with trait anxiety in the LOGOS and additionally the recruits with higher PRSSZ and trait anxiety exhibited attenuated paranoid ideation. Together, these findings do not support an etiological link between increased polygenic liability for SZ and schizotypy, suggesting that psychosocial stress or trait anxiety may impact schizotypal phenotypic expressions among healthy young adults not genetically predisposed to SZ.

The Student Counselling Centre at the University of Crete, Greece.

This report describes the Student Counselling Centre (SCC) at the University of Crete. The SCS was established in 2003. Its main areas of activity are individual and group psychological support, crisis intervention, research, prevention, volunteering and awareness. Emphasis is also put on the support provided to students with special needs, which is now the second core service of the SCC.

Maternal depression and personality traits in association with child neuropsychological and behavioral development in preschool years: Mother-child cohort (Rhea Study) in Crete, Greece.

BACKGROUND: Poor perinatal maternal mental health has been linked with negative outcomes on early child development; however, the importance of maternal personality has been neglected thus far. We aimed to examine the effects of antenatal and postnatal maternal mental health, including assessment of maternal personality characteristics, on child neuropsychological and behavioral development at preschool years in a population based mother-child cohort (Rhea Study) in Crete, Greece. METHOD: Self-reported measures of maternal depression (EPDS), trait anxiety (STAI-Trait) and personality traits (EPQ-R) were assessed in a sample of 288 women at 28-32 weeks of gestation. A larger sample of 642 mothers completed the EPDS scale at 8 weeks postpartum. Children's neuropsychological (MSCA) and behavioral (ADHDT and SDQ) development were assessed at 4 years of age. Linear regression analyses were used to estimate the associations between the exposures and outcomes of interest after adjustment for potential confounders. RESULTS: Regarding child neuropsychological development, increased postnatal depressive symptoms were associated with child's perceptual performance, whereas increased maternal psychoticism was linked with child's motor ability at 4 years of age. Furthermore, elevated levels of maternal depression during pregnancy and postpartum, and the predisposing personality characteristics of trait anxiety and neuroticism, were associated with children's behavioral difficulties. LIMITATIONS: A clinical diagnostic instrument for maternal mental health was not used and assessment of children's behavior was based on maternal report. CONCLUSION: These findings suggest that poor perinatal maternal mental health and an adverse personality profile may be associated with impaired child neuropsychological and behavioral development at preschool years.

Neurocognitive performance, psychopathology and social functioning in individuals at high risk for schizophrenia or psychotic bipolar disorder.

INTRODUCTION: Although cognitive deficits are consistent endophenotypes of schizophrenia and bipolar disorder, findings in psychotic bipolar disorder (BDP) are inconsistent. In this study we compared adult unaffected first-degree relatives of schizophrenia and BDP patients on cognition, psychopathology, social functioning and quality of life. METHODS: Sixty-six unaffected first-degree relatives of schizophrenia patients (SUnR), 36 unaffected first-degree relatives of BDP patients (BDPUnR) and 102 controls participated in the study. Between-group differences were examined and Discriminant Function Analysis (DFA) predicted group membership. RESULTS: Visual memory, control inhibition, working memory, cognitive flexibility and abstract reasoning were linearly impaired in the relatives' groups. Poorer verbal fluency and processing speed were evident only in the SUnR group. The SUnR group had higher depressive and somatization symptoms while the BDPUnR group had higher anxiety and lower social functioning compared with the controls. Individuals with superior cognition were more likely to be classified as controls; those with higher social functioning, prolonged processing speed and lower anxiety were more likely to be classified as SUnR. LIMITATIONS: The relatives' sample is quite heterogeneous; the effects of genetic or environmental risk-factors were not examined. CONCLUSIONS: Cognitive functions mediated by a fronto-parietal network, show linear impairments in unaffected relatives of BDP and schizophrenia patients; processing speed and verbal fluency impairments were evident only in schizophrenia relatives. Self-perceived symptomatology and social functioning also differ between schizophrenia and BDP relatives. The continuum seen in patients in several indices was also seen in the cognitive impairments in unaffected relatives of schizophrenia and BDP patients.

Epidemiological Differences Between Localized and Nonlocalized Low Back Pain.

STUDY DESIGN: A cross-sectional survey with a longitudinal follow-up. OBJECTIVES: The aim of this study was to test the hypothesis that pain, which is localized to the low back, differs epidemiologically from that which occurs simultaneously or close in time to pain at other anatomical sites SUMMARY OF BACKGROUND DATA.: Low back pain (LBP) often occurs in combination with other regional pain, with which it shares similar psychological and psychosocial risk factors. However, few previous epidemiological studies of LBP have distinguished pain that is confined to the low back from that which occurs as part of a wider distribution of pain. METHODS: We analyzed data from CUPID, a cohort study that used baseline and follow-up questionnaires to collect information about musculoskeletal pain, associated disability, and potential risk factors, in 47 occupational groups (office workers, nurses, and others) from 18 countries. RESULTS: Among 12,197 subjects at baseline, 609 (4.9%) reported localized LBP in the past month, and 3820 (31.3%) nonlocalized LBP. Nonlocalized LBP was more frequently associated with sciatica in the past month (48.1% vs. 30.0% of cases), occurred on more days in the past month and past year, was more often disabling for everyday activities (64.1% vs. 47.3% of cases), and had more frequently led to medical consultation and sickness absence from work. It was also more often persistent when participants were followed up after a mean of 14 months (65.6% vs. 54.1% of cases). In adjusted Poisson regression analyses, nonlocalized LBP was differentially associated with risk factors, particularly female sex, older age, and somatizing tendency. There were also marked differences in the relative prevalence of localized and nonlocalized LBP by occupational group. CONCLUSION: Future epidemiological studies should distinguish where possible between pain that is limited to the low back and LBP that occurs in association with pain at other anatomical locations. LEVEL OF EVIDENCE: 2.

Prenatal exposure to persistent organic pollutants in association with offspring neuropsychological development at 4years of age: The Rhea mother-child cohort, Crete, Greece.

BACKGROUND: Persistent Organic Pollutants (POPs) are highly-resistant compounds to environmental degradation and due to fat solubility they bioaccumulate through the food chain. As they cross the placenta, in utero exposure to POPs could disrupt child neurodevelopment as they are considered to be neurotoxic. AIMS: We examined whether in utero exposure to levels of different POPs is associated with offspring cognitive and behavioral outcomes at 4years of age in a mother-child cohort in Crete, Greece (Rhea study). METHODS: We included 689 mother-child pairs. Concentrations of several polychlorinated biphenyls (PCBs) and other organochlorine compounds (dichlorodiphenyl dichloroethene [DDE], hexachlorobenzene [HCB]) were determined in maternal serum collected in the first trimester of pregnancy by triple quadrupole mass spectrometry. Neurodevelopment at 4years was assessed by means of the McCarthy Scales of Children's Abilities. Behavioral difficulties were assessed by Strengths and Difficulties Questionnaire and Attention Deficit Hyperactivity Disorder Test. Linear regression analyses were used to estimate the associations between the exposures and outcomes of interest after adjustment for potential confounders. RESULTS: Children with "high" HCB concentrations (≥90th percentile) in maternal serum, demonstrated decreased scores in perceptual performance (adjusted ß=-6.07; 95% CI: -10.17, -1.97), general cognitive (adjusted ß=-4.97; 95% CI: -8.99, -0.96), executive function (adjusted ß=-6.24; 95% CI: -10.36, -2.11) and working memory (adjusted ß=-4.71; 95% CI: -9.05, -0.36) scales at 4years of age. High exposure to PCBs (≥90th percentile) during pregnancy was associated with a 4.62 points reduction in working memory score at 4years of age (95% CI: -9.10, -0.14). Prenatal exposure to DDE, HCB and PCBs was not associated with child behavioral difficulties. CONCLUSIONS: The findings suggest that prenatal exposure to HCB and PCBs may contribute to reduced cognitive development at preschool age. Our results raise the possibility that exposure to HCB may play a more important role in child cognition than previously considered.

Associations of differential schizotypal dimensions with executive working memory: A moderated-mediation analysis.

BACKGROUND: Increased schizotypal traits are observed in a percentage of the general population and in the schizophrenia-spectrum and have been associated with impairments in working memory. In this study we examined the effects of four schizotypal dimensions [Negative (NegS), Paranoid (ParS), Cognitive-Perceptual (CPS), Disorganized (DiS)] on executive working memory (EWM), as mediated by set-shifting, planning and control inhibition. We also examined whether these associations are moderated by family-history of psychosis. METHODS: Our sample consisted of 110 unaffected first-degree relatives of schizophrenia-spectrum patients and 120 control individuals. Schizotypy was assessed with the Schizotypal Personality Questionnaire. Participants were also tested with the Letter-Number Sequencing, Wisconsin Card Sorting, Stroop Color-Word and Stockings of Cambridge tasks. The effects of set-shifting, control inhibition and planning on the relationship between schizotypy and EWM were examined with mediation analyses. Moderated-mediation analyses examined potential moderating effects of group membership (unaffected relative/community participant). RESULTS: All mediators were significant in the relationship between NegS and EWM. The effects of ParS were mediated only by set-shifting and planning. Planning and control inhibition were the only significant mediators on the effects of CPS and DiS on EWM, respectively. The moderated-mediation analyses revealed that these findings apply only in the community group. CONCLUSIONS: We found that the effects of different schizotypal dimensions on EWM are mediated by other cognitive processes in individuals without personal/family history of psychosis. This is probably due to either more severe impairments in the cognitive processes of the relatives or restrictions in our sample and study-design.

Cognitive profiles of schizotypal dimensions in a community cohort: Common properties of differential manifestations.

INTRODUCTION: Studies assessing the effects of schizotypal dimensions (i.e., positive, negative, and disorganized) on cognitive functions have yielded mixed findings. In the present study, we administered an extensive battery of cognitive tasks to a community sample and defined the schizotypal dimensions according to a more analytical four-factor model, whereby positive schizotypy is further divided into cognitive-perceptual and paranoid. METHOD: Two hundred healthy community participants were assessed for schizotypy with the Schizotypal Personality Questionnaire; assessment of cognitive functions included set shifting, working memory, processing speed, verbal fluency, attention switching, planning/problem solving, strategy formation, and abstract reasoning. Associations between cognitive tasks and schizotypy were examined with hierarchical multiple linear regressions. We also divided our subjects into groups based on whether or not their scores in the negative, positive, and cognitive-perceptual factors fell in the upper 10% of the scores of a large community normative sample in Greece and examined between-group differences. RESULTS: Applying both dimensional and categorical approaches, we showed that (a) attention-switching impairment is a "core" deficit of both negative and paranoid schizotypy, (b) impaired working memory and set shifting are associated mainly with negative and to a lesser extent paranoid schizotypy, (c) paranoid schizotypy is associated with reduced performance in tasks requiring intact frontotemporal connectivity, and (d) cognitive-perceptual and disorganized schizotypy are not associated with any cognitive functions. CONCLUSIONS: Our findings further support the more analytical four-factor categorization of schizotypy and suggest that the discrepancies in the findings so far might be due to a more "generalized" definition of the schizotypal dimensions. They also add further in the early formulation of the profile of the high-schizotypal individuals seeking psychiatric help so that their overall management is directed towards a more targeted approach.

Descriptive Epidemiology of Somatising Tendency: Findings from the CUPID Study.

Somatising tendency, defined as a predisposition to worry about common somatic symptoms, is importantly associated with various aspects of health and health-related behaviour, including musculoskeletal pain and associated disability. To explore its epidemiological characteristics, and how it can be specified most efficiently, we analysed data from an international longitudinal study. A baseline questionnaire, which included questions from the Brief Symptom Inventory about seven common symptoms, was completed by 12,072 participants aged 20-59 from 46 occupational groups in 18 countries (response rate 70%). The seven symptoms were all mutually associated (odds ratios for pairwise associations 3.4 to 9.3), and each contributed to a measure of somatising tendency that exhibited an exposure-response relationship both with multi-site pain (prevalence rate ratios up to six), and also with sickness absence for non-musculoskeletal reasons. In most participants, the level of somatising tendency was little changed when reassessed after a mean interval of 14 months (75% having a change of 0 or 1 in their symptom count), although the specific symptoms reported at follow-up often differed from those at baseline. Somatising tendency was more common in women than men, especially at older ages, and varied markedly across the 46 occupational groups studied, with higher rates in South and Central America. It was weakly associated with smoking, but not with level of education. Our study supports the use of questions from the Brief Symptom Inventory as a method for measuring somatising tendency, and suggests that in adults of working age, it is a fairly stable trait.

Classification of neck/shoulder pain in epidemiological research: a comparison of personal and occupational characteristics, disability, and prognosis among 12,195 workers from 18 countries.

To inform case definition for neck/shoulder pain in epidemiological research, we compared levels of disability, patterns of association, and prognosis for pain that was limited to the neck or shoulders (LNSP) and more generalised musculoskeletal pain that involved the neck or shoulder(s) (GPNS). Baseline data on musculoskeletal pain, disability, and potential correlates were collected by questionnaire from 12,195 workers in 47 occupational groups (mostly office workers, nurses, and manual workers) in 18 countries (response rate = 70%). Continuing pain after a mean interval of 14 months was ascertained through a follow-up questionnaire in 9150 workers from 45 occupational groups. Associations with personal and occupational factors were assessed by Poisson regression and summarised by prevalence rate ratios (PRRs). The 1-month prevalence of GPNS at baseline was much greater than that of LNSP (35.1% vs 5.6%), and it tended to be more troublesome and disabling. Unlike LNSP, the prevalence of GPNS increased with age. Moreover, it showed significantly stronger associations with somatising tendency (PRR 1.6 vs 1.3) and poor mental health (PRR 1.3 vs 1.1); greater variation between the occupational groups studied (prevalence ranging from 0% to 67.6%) that correlated poorly with the variation in LNSP; and was more persistent at follow-up (72.1% vs 61.7%). Our findings highlight important epidemiological distinctions between subcategories of neck/shoulder pain. In future epidemiological research that bases case definitions on symptoms, it would be useful to distinguish pain that is localised to the neck or shoulder from more generalised pain that happens to involve the neck/shoulder region.

The Relationship of Common Risk Variants and Polygenic Risk for Schizophrenia to Sensorimotor Gating.

BACKGROUND: Prepulse inhibition (PPI) of the startle reflex has been suggested as a candidate endophenotype for schizophrenia research, as it shows high heritability and has been found deficient in schizophrenia spectrum disorders. The objectives of the study were to 1) identify common genetic variants associated with baseline startle and PPI; 2) estimate the single nucleotide polymorphism heritability; and 3) examine the relationship of polygenic score for schizophrenia with baseline startle and PPI. METHODS: A cohort of healthy young male subjects (n = 1493) originating from the Learning on Genetics of Schizophrenia Spectrum project was assessed for baseline startle and PPI. The most recent genome-wide association study in schizophrenia from the Psychiatric Genomics Consortium 2 was used to calculate polygenic scores. RESULTS: Eleven loci showed suggestive association (p < 10(-6)) with baseline startle and PPI in the discovery cohort. Additional genotyping in a replication cohort identified genome-wide significant association at two loci (rs61810702 and rs4718984). These loci were co-localized with expression quantitative trait loci associated with gene expression of nerve growth factor (NGF) and calneuron 1 (CALN1) genes. Estimation of the genetic and environmental contributions to baseline startle and PPI showed a substantial single nucleotide polymorphism heritability for 120-ms PPI stimuli. Increased polygenic risk score for schizophrenia was associated with reduced PPI. CONCLUSIONS: Common genetic variation has an important role in the etiology of schizophrenia and PPI impairments. Overall, these data support the idea that PPI is a valid endophenotype that can be used to explore the genetic architecture of schizophrenia.

Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood.

Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome-wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow-up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome-wide single-nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta-analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC-SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation-based analysis revealed an excess of strongly associated loci among GWAS top-ranked signals for verbal working memory (WM) and antisaccade intra-subject reaction time variability (empirical P < 0.001), suggesting multiple true-positive single-SNP associations. Substantial heritability was observed for WM performance. Further, sustained attention/vigilance and WM were suggestively correlated with both COGENT and PGC-SZ derived polygenic scores. Overall, these results imply that common genetic variation explains some of the variability in neurocognitive functioning among young adults, particularly WM, and provide supportive evidence that increased SZ genetic risk predicts neurocognitive fluctuations in the general population.

Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment.

Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.