Gene–environment interaction study on the polygenic risk score for neuroticism, childhood adversity, and parental bonding

The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRSN), in interaction with bullying, parental bonding, and childhood adversity. Data were derived from a general population adolescent and young adult twin cohort. The final sample consisted of 202 monozygotic and 436 dizygotic twins and 319 twin pairs. The Short Eysenck Personality questionnaire was used to measure neuroticism. PRSN was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRSN. Multilevel mixed-effects models were used to analyze the main and interacting associations of PRSN, childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene–environment correlation. PRSN thresholds of .005 and .2 were chosen, based on GPC and UKB datasets, respectively. After correction for confounders, all the individual variables were associated with the expression of neuroticism: both PRSN from GPC and UKB, childhood adversity, maternal bonding, paternal bonding, and bullying in primary school and secondary school. However, the results indicated no evidence for gene–environment interaction in this cohort. These results suggest that genetic vulnerability on the one hand and negative life events (childhood adversity and bullying) and positive life events (optimal parental bonding) on the other represent noninteracting pathways to neuroticism

Age- and sex-specific associations between risk scores for schizophrenia and self-reported health in the general population

Purpose The health correlates of polygenic risk (PRS-SCZ) and exposome (ES-SCZ) scores for schizophrenia may vary depending on age and sex. We aimed to examine age- and sex-specific associations of PRS-SCZ and ES-SCZ with self-reported health in the general population. Methods Participants were from the population-based Netherlands Mental Health Survey and Incidence Study–2 (NEMESIS-2). Mental and physical health were measured with the 36-item Short Form Survey 4 times between 2007 and 2018. The PRS-SCZ and ES-SCZ were respectively calculated from common genetic variants and exposures (cannabis use, winter birth, hearing impairment, and five childhood adversity categories). Moderation by age and sex was examined in linear mixed models. Results For PRS-SCZ and ES-SCZ analyses, we included 3099 and 6264 participants, respectively (age range 18–65 years; 55.7–56.1% female). Age and sex did not interact with PRS-SCZ. Age moderated the association between ES-SCZ and mental (interaction: p = 0.02) and physical health (p = 0.0007): at age 18, + 1.00 of ES-SCZ was associated with − 0.10 of mental health and − 0.08 of physical health, whereas at age 65, it was associated with − 0.21 and − 0.23, respectively (all units in standard deviations). Sex moderated the association between ES-SCZ and physical health (p < .0001): + 1.00 of ES-SCZ was associated with − 0.19 of physical health among female and − 0.11 among male individuals. Conclusion There were larger associations between higher ES-SCZ and poorer health among female and older individuals. Accounting for these interactions may increase ES-SCZ precision and help uncover populational determinants of environmental influences on health

Replicated evidence that endophenotypic expression of schizophrenia polygenic risk is greater in healthy siblings of patients compared to controls, suggesting gene-environment interaction. The EUGEI study

Background First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes. Methods We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS. Results In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group. Conclusions The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder

Examining the association between exposome score for schizophrenia and functioning in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

Background. A cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls. Methods. This cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate. Results. ES-SCZ was associated with the GAF dimensions in patients (symptom: B = 1.53, p-value = 0.001; disability: B = 1.44, p-value = 0.001), siblings (symptom: B = 3.07, p-value < 0.001; disability: B = 2.52, p-value < 0.001), and healthy controls (symptom: B = 1.50, p-value < 0.001; disability: B = 1.31, p-value < 0.001). The results remained the same after adjusting for PRS-SCZ. The degree of associations of ES-SCZ with both symptom and disability dimensions were higher in unaffected siblings than in patients and controls. By analyzing an independent dataset (the Genetic Risk and Outcome of Psychosis study), we replicated the results observed in the patient group. Conclusions. Our findings suggest that ES-SCZ shows promise for enhancing risk prediction and stratification in research practice. From a clinical perspective, ES-SCZ may aid in efforts of clinical characterization, operationalizing transdiagnostic clinical staging models, and personalizing clinical management

Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: results from the EUGEI study

Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxy‐genetic liability measures suggest gene‐environment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRS‐SCZ) and environmental exposures in 1,699 patients with a diagnosis of schizophrenia spectrum disorders and 1,542 unrelated controls with no lifetime history of a diagnosis of those disorders, we provide further evidence for gene‐environment interaction in schizophrenia. Evidence was found for additive interaction of molecular genetic risk state for schizophrenia (binary mode of PRS‐SCZ above 75% of the control distribution) with the presence of lifetime regular cannabis use and exposure to early‐life adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of hearing impairment, season of birth (winter birth), and exposure to physical abuse or physical neglect in childhood. The sensitivity analyses replacing the a priori PRS‐SCZ at 75% with alternative cut‐points (50% and 25%) confirmed the additive interaction. Our results suggest that the etiopathogenesis of schizophrenia involves genetic underpinnings that act by making individuals more sensitive to the effects of some environmental exposures

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes

Common Genetic Variation And Age at Onset Of Anorexia Nervosa

Background Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed which included 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at onset, early-onset AN (< 13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (SNP-h2) were 0.01-0.04 for age at onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age at onset and early-onset AN estimated from independent GWASs significantly predicted age at onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions Our results provide evidence consistent with a common variant genetic basis for age at onset and implicate biological pathways regulating menarche and reproduction.Peer reviewe

Clustering schizophrenia genes by their temporal expression patterns aids functional interpretation

Background Schizophrenia is a highly heritable brain disorder with a typical symptom onset in early adulthood. The 2-hit hypothesis posits that schizophrenia results from differential early neurodevelopment, predisposing an individual, followed by a disruption of later brain maturational processes that trigger the onset of symptoms. Study design We applied hierarchical clustering to transcription levels of 345 genes previously linked to schizophrenia, derived from cortical tissue samples from 56 donors across the lifespan. We subsequently calculated clustered-specific polygenic risk scores for 743 individuals with schizophrenia and 743 sex- and age-matched healthy controls. Study results Clustering revealed a set of 183 genes that was significantly upregulated prenatally and downregulated postnatally and 162 genes that showed the opposite pattern. The prenatally upregulated set of genes was functionally annotated to fundamental cell cycle processes, while the postnatally upregulated set was associated with the immune system and neuronal communication. We found an interaction between the 2 scores; higher prenatal polygenic risk showed a stronger association with schizophrenia diagnosis at higher levels of postnatal polygenic risk. Importantly, this finding was replicated in an independent clinical cohort of 3233 individuals. Conclusions We provide genetics-based evidence that schizophrenia is shaped by disruptions of separable biological processes acting at distinct phases of neurodevelopment. The modeling of genetic risk factors that moderate each other’s effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

White noise speech illusions: A trait-dependent risk marker for psychotic disorder?

Introduction: White noise speech illusions index liability for psychotic disorder in case-control comparisons. In the current study, we examined i) the rate of white noise speech illusions in siblings of patients with psychotic disorder and ii) to what degree this rate would be contingent on exposure to known environmental risk factors (childhood adversity and recent life events) and level of known endophenotypic dimensions of psychotic disorder [psychotic experiences assessed with the Community Assessment of Psychic Experiences (CAPE) scale and cognitive ability]. Methods: The white noise task was used as an experimental paradigm to elicit and measure speech illusions in 1,014 patients with psychotic disorders, 1,157 siblings, and 1,507 healthy participants. We examined associations between speech illusions and increasing familial risk (control -> sibling -> patient), modeled as both a linear and a categorical effect, and associations between speech illusions and level of childhood adversities and life events as well as with CAPE scores and cognitive ability scores. Results: While a positive association was found between white noise speech illusions across hypothesized increasing levels of familial risk (controls -> siblings -> patients) [odds ratio (OR) linear 1.11, 95% confidence interval (CI) 1.02-1.21, p = 0.019], there was no evidence for a categorical association with sibling status (OR 0.93, 95% CI 0.79-1.09, p = 0.360). The association between speech illusions and linear familial risk was greater if scores on the CAPE positive scale were higher (p interaction = 0.003; ORlow CAPE positive scale 0.96, 95% CI 0.85-1.07; ORhigh CAPE positive scale 1.26, 95% CI 1.09-1.46); cognitive ability was lower (p interaction < 0.001; ORhigh cognitive ability 0.94, 95% CI 0.84-1.05; ORlow cognitive ability 1.43, 95% CI 1.23-1.68); and exposure to childhood adversity was higher (p interaction < 0.001; ORlow adversity 0.92, 95% CI 0.82-1.04; ORhigh adversity 1.31, 95% CI 1.13-1.52). A similar, although less marked, pattern was seen for categorical patient-control and sibling-control comparisons. Exposure to recent life events did not modify the association between white noise and familial risk (p interaction = 0.232). Conclusion: The association between white noise speech illusions and familial risk is contingent on additional evidence of endophenotypic expression and of exposure to childhood adversity. Therefore, speech illusions may represent a trait-dependent risk marker