Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Hatzimanolis A

PROVIDER: S-EPMC5814832 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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

Hatzimanolis Alex A Avramopoulos Dimitrios D Arking Dan E DE Moes Anna A Bhatnagar Pallav P Lencz Todd T Malhotra Anil K AK Giakoumaki Stella G SG Roussos Panos P Smyrnis Nikolaos N Bitsios Panos P Stefanis Nicholas C NC

Schizophrenia bulletin 20180201 2

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 Gen ...[more]

PMID: 29036523

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Project description:ImportanceBetween-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature.ObjectivesTo compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls.Design, setting, and participantsThis case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018.Main outcomes and measuresMean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality.ResultsA comparison of 1151 patients with schizophrenia (mean [SD] age, 33.8 [10.6] years; 68.6% male [n = 790] and 31.4% female [n = 361]) with 2010 healthy controls (mean [SD] age, 32.6 [10.4] years; 56.0% male [n = 1126] and 44.0% female [n = 884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t = 3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age, 55.9 [7.5] years; 48.2% male [n = 6025] and 51.8% female [n = 6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t = -3.00) but was not significantly associated with dispersion.Conclusions and relevanceThis study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia.

Project description:BACKGROUND:A recent large-scale mega genome-wide association study identified, for the first time, genetic variants at 12 loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). In this study we use a powerful polygenic approach, with polygenic scores derived from the genome-wide association study, to investigate the etiological overlap between ADHD and frequently co-occurring traits and disorders. METHODS:Polygenic risk scores for ADHD derived from the mega genome-wide association study (20,183 cases and 35,191 control subjects) were computed in a large-scale adult population sample (N = 135,726) recruited by the UK Biobank. Regression analyses were conducted to investigate whether polygenic risk for ADHD is associated with related traits and disorders in this population sample. The effects of sex were investigated via inclusion of an interaction term in the models. RESULTS:Polygenic risk for ADHD significantly and positively predicted body mass index (R2 = .45%; p = 5 × 10-129), neuroticism (R2 = .09%; p = 2 × 10-24), depression (R2 = .11%; p = 2 × 10-13), anxiety (R2 = .06%; p = 3 × 10-4), risk taking (R2 = .12%; p = 9 × 10-25), alcohol intake (R2 = .09%; p = 8 × 10-29), smoking (R2 = .33%; p = 4 × 10-21), alcohol dependency (R2 = .21%; p = 5 × 10-6), and negatively predicted verbal-numerical reasoning (R2 = .38%; p = 5 × 10-36). Polygenic risk scores did not significantly predict schizophrenia or bipolar disorder, although this may be because of the small number of diagnostic cases. We found no interaction effects between polygenic risk for ADHD and sex on any phenotypes. CONCLUSIONS:Our findings suggest that common genetic variation underlying risk for clinically diagnosed ADHD also contributes to higher body mass index, neuroticism, anxiety and depressive disorders, alcohol and nicotine use, risk taking, and lower general cognitive ability in the general population. These findings suggest that the co-occurrence of several traits with ADHD is partly explained by the same common genetic variants.

Project description: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.

Project description:Perceptual organization (PO) difficulties have repeatedly been reported in people with schizophrenia, and in healthy individuals with high levels of schizotypy traits, who are at increased risk for schizophrenia. In particular, poor performance on the Embedded Figures Test (EFT) has been interpreted as an atypically strong preference for global over local processing, even though these processes cannot be clearly disambiguated on this test. Here we use two separate versions of the Radial Frequency Search Task (RFST), a new index of PO abilities, to selectively investigate global and local processing of shape information in trait schizotypy. Schizotypy traits were assessed using the Wisconsin Schizotypy Scales-Brief. Individuals selected for high and low levels of positive schizotypy [assessed with the Wisconsin Schizotypy Scales-Brief Perceptual Aberration (PAb) scale] completed the EFT, along with the Global RFST and the Local RFST, all of which require participants to find a target shape amongst distractor elements. The High PAb group (n = 83) were less efficient (i.e., reactions times slowed more as the set size increased) than the Low PAb group (n = 146) on the Global RFST (significant group differences for Target Absent conditions only), but not the Local RFST. High and Low PAb groups also differed on other schizotypy traits, so the specificity of the results to positive schizotypy cannot be assured. Unexpectedly, no group differences were observed on the EFT; however, there was a small, but significant, positive correlation between RFST search efficiency and EFT performance, indicating that they shared some common processes. Overall, the pattern of results suggests that global (but not local) processing difficulties may be contributing to the poorer perceptual organization observed in groups with high levels of schizotypy traits. In addition, the confinement of this result to the Target Absent condition suggests that the underlying mechanism involves differences in decisional processes on the RFST between high and low schizotypy groups. The RFST shows promise as a useful tool for measuring specific perceptual organization abilities in non-clinical, and potentially clinical, samples.

Project description:Importance:Schizophrenia is a highly heritable psychiatric disorder, and recent studies have suggested that exposure to nitrogen dioxide (NO2) during childhood is associated with an elevated risk of subsequently developing schizophrenia. However, it is not known whether the increased risk associated with NO2 exposure is owing to a greater genetic liability among those exposed to highest NO2 levels. Objective:To examine the associations between childhood NO2 exposure and genetic liability for schizophrenia (as measured by a polygenic risk score), and risk of developing schizophrenia. Design, Setting, and Participants:Population-based cohort study including individuals with schizophrenia (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code F20) and a randomly selected subcohort. Using national registry data, all individuals born in Denmark between May 1, 1981, and December 31, 2002, were followed up from their 10th birthday until the first occurrence of schizophrenia, emigration, death, or December 31, 2012, whichever came first. Statistical analyses were conducted between October 24, 2018, and June 17, 2019. Exposures:Individual exposure to NO2 during childhood estimated as mean daily exposure to NO2 at residential addresses from birth to the 10th birthday. Polygenic risk scores were calculated as the weighted sum of risk alleles at selected single-nucleotide polymorphisms based on genetic material obtained from dried blood spot samples from the Danish Newborn Screening Biobank and on the Psychiatric Genomics Consortium genome-wide association study summary statistics file. Main Outcomes and Measures:The main outcome was schizophrenia. Weighted Cox proportional hazards regression models were fitted to estimate adjusted hazard ratios (AHRs) for schizophrenia with 95% CIs according to the exposures. Results:Of a total of 23?355 individuals, 11?976 (51.3%) were male and all had Danish-born parents. During the period of the study, 3531 were diagnosed with schizophrenia. Higher polygenic risk scores were correlated with higher childhood NO2 exposure (??=?0.0782; 95% CI, 0.065-0.091; P?<?.001). A 10-?g/m3 increase in childhood daily NO2 exposure (AHR, 1.23; 95% CI, 1.15-1.32) and a 1-SD increase in polygenic risk score (AHR, 1.29; 95% CI, 1.23-1.35) were independently associated with increased schizophrenia risk. Conclusions and Relevance:These findings suggest that the apparent association between NO2 exposure and schizophrenia is only slightly confounded by a higher polygenic risk score for schizophrenia among individuals living in areas with greater NO2. The findings demonstrate the utility of including polygenic risk scores in epidemiologic studies.

Dataset Information

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

Publications

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

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