Environmental Risk Factors for Schizophrenia and Bipolar Disorder and Their Relationship to Genetic Risk: Current Knowledge and Future Directions

Frontiers in Genetics, Journal Year: 2021, Volume and Issue: 12

Published: June 28, 2021

Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric disorders which result from complex interplay between genetic environmental factors. It is well-established that they highly heritable disorders, considerable progress has been made identifying their shared distinct risk However, the 15-40% of derived sources less definitively known. Environmental factors have repeatedly investigated often associated with SZ include: obstetric complications, infections, winter or spring birth, migration, urban living, childhood adversity, cannabis use. There evidence adversity some types infections also BD. Evidence for other in BD weaker due to fewer studies smaller sample sizes. Relatively few exposures ever examined BD, additional ones likely remain be discovered. A complete picture how confer these requires an understanding interact. Early gene-by-environment interaction both involved candidate genes were underpowered. Larger samples genome-wide data polygenic scores now offer enhanced prospects reveal interactions contribute disorders. Overall, although identified SZ, extent account total remains unknown. For not well understood merit further investigation. Questions regarding mechanisms by exert effects, ways differ sex. Concurrent investigations needed as we work toward a more comprehensive arise.

Language: Английский

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Prioritization of potential causative genes for schizophrenia in placenta

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 15, 2023

Abstract Our earlier work has shown that genomic risk for schizophrenia converges with early life complications in affecting the disorder and sex-biased neurodevelopmental trajectories. Here, we identify specific genes potential mechanisms that, placenta, may mediate such outcomes. We performed TWAS healthy term placentae ( N = 147) to derive candidate placental causal confirmed SMR; search placenta schizophrenia-specific associations, an analogous analysis fetal brain 166) additional other disorders/traits. The analyses whole sample stratifying by sex ultimately highlight 139 genes, many being sex-biased; molecular converge on nutrient-sensing capabilities of trophoblast invasiveness. These also implicate Coronavirus-pathogenesis pathway showed increased expression from a small SARS-CoV-2-positive pregnancies. Investigating lead opportunities prevention would not be suggested study alone.

Language: Английский

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High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(49)

Published: Nov. 27, 2023

Exposure to stressful life events increases the risk for psychiatric disorders. Mechanistic insight into genetic factors moderating impact of stress can increase our understanding disease processes. Here, we test 3,662 single nucleotide polymorphisms (SNPs) from preselected expression quantitative trait loci in massively parallel reporter assays identify variants that modulate activity regulatory elements sensitive glucocorticoids, important mediators response. Of tested SNP sequences, 547 were located glucocorticoid-responsive which 233 showed allele-dependent activity. Transcripts regulated by these functional enriched those differentially expressed disorders postmortem brain. Phenome-wide Mendelian randomization analysis 4,439 phenotypes revealed potentially causal associations specifically neurobehavioral traits, including major depression and other Finally, a gene score derived was significantly associated with differences physiological response, suggesting may alter individual set point

Language: Английский

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Demographic, Premorbid, and Clinical Characteristics of Schizophrenia Spectrum Patients with High and Low Polygenic Liability to the Disorder

Diseases, Journal Year: 2025, Volume and Issue: 13(3), P. 66 - 66

Published: Feb. 21, 2025

Background/Objectives: Schizophrenia is a clinically heterogeneous complex disorder with substantial polygenic basis. The discovery of phenotypes indexing genetic differences advances research into the schizophrenia etiology but has proven to be challenging. study aimed further clarify relationships risk scores (SZ-PRSs) comprehensive array antecedents and presentations using culturally ethnically homogeneous sample spectrum patients. Methods: top bottom deciles (n = 172) SZ-PRS distribution in group 861 patients were compared on information derived from medical records logistic regression. Results: High SZ-PRSs associated female sex, family history wide range neuropsychiatric conditions, moderately poor premorbid social cognitive adjustment childhood, diagnosis, positive “abnormal” psychomotor symptoms. low-SZ-PRS demonstrated an accumulation both individuals milder forms SZ disorders those severe abnormalities social, cognitive, neurological domains. Conclusions: results highlight as characteristic manifestations component provide first piece PRS-based evidence for long-standing idea higher liability threshold women. presence cases decile, suggesting its etiological heterogeneity, might important source inconsistency previous SZ-PRSs’ relationship should considered future studies.

Language: Английский

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A Genome-Wide Association Study of First-Episode Psychosis: A Genetic Exploration in an Italian Cohort

Genes, Journal Year: 2025, Volume and Issue: 16(4), P. 439 - 439

Published: April 7, 2025

Background: Psychosis, particularly schizophrenia (SZ), is influenced by genetic and environmental factors. The neurodevelopmental hypothesis suggests that factors affect neuronal circuit connectivity during perinatal periods, hence causing the onset of diseases. In this study, we performed a genome-wide association study (GWAS) in sample first episode psychosis (FEP). Methods: A 147 individuals diagnosed with non-affective 102 controls were recruited assessed. After venous blood DNA extraction, samples genotyped. Genetic data underwent quality controls, genotype imputation, case-control (GWAS). GWAS, results investigated using an silico functional mapping annotation approach. Results: Our GWAS showed 27 variants across 13 chromosomes at significance (p < 1 × 10−7) total 1976 candidate 188 genes suggestive 10−5), mostly non-coding or intergenic regions. Gene-based tests reported SUFU = 4.8 NCAN 1.6 10−5) genes. Gene-sets enrichment analyses associations early stages life, spanning from 12 to 24 post-conception weeks 1.4 10−3) late prenatal period 10−3), favor hypothesis. Moreover, several matches Catalog strictly related traits, such as SZ, well autism spectrum disorder, which shares some overlap, risk factors, neuroticism alcohol dependence. Conclusions: resulting consequent analysis displayed common liability between psychosis, sum, our investigation provided novel hints supporting SZ and—in general—in psychoses.

Language: Английский

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Effect of polygenic risk score, family load of schizophrenia and exposome risk score, and their interactions, on the long-term outcome of first-episode psychosis

Psychological Medicine, Journal Year: 2023, Volume and Issue: 53(14), P. 6838 - 6847

Published: March 6, 2023

Abstract Background Consistent evidence supports the involvement of genetic and environmental factors, their interactions, in etiology psychosis. First-episode psychosis (FEP) comprises a group disorders that show great clinical long-term outcome heterogeneity, extent to which genetic, familial factors account for predicting FEP patients remains scarcely known. Methods The SEGPEPs is an inception cohort study 243 first-admission with who were followed-up mean 20.9 years. thoroughly evaluated by standardized instruments, 164 providing DNA. Aggregate scores estimated large populations polygenic risk score (PRS-Sz), exposome (ERS-Sz) load schizophrenia (FLS-Sz) ascertained. Long-term functioning was assessed means Social Occupational Functioning Assessment Scale (SOFAS). relative excess due interaction (RERI) used as standard method estimate effect factors. Results Our results showed high FLS-Sz gave greater explanatory capacity outcome, followed ERS-Sz then PRS-Sz. PRS-Sz did not discriminate significantly between recovered non-recovered long term. No significant PRS-Sz, or regarding found. Conclusions support additive model antecedents schizophrenia, contributors poor functional patients.

Language: Английский

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Cell type-specific and cross-population polygenic risk score analyses of MIR137 gene pathway in schizophrenia

iScience, Journal Year: 2021, Volume and Issue: 24(7), P. 102785 - 102785

Published: June 25, 2021

Cell type-specific pathway-based polygenic risk scores (PRSs) may better inform disease biology and improve the precision of PRS-based clinical prediction. For microRNA-137 (MIR137), a leading neuropsychiatric gene post-transcriptional master regulator, we conducted cell set PRS analysis in both European Han Chinese schizophrenia (SZ) samples. We found that neuronal MIR137-target genes explains SZ than derived from iPSC or reported sets showing MIR137-altered expression. Compared with whole genome target TCF4, explained disproportionally larger (relative to SNP number) sample, but more modest advantage sample. Our study demonstrated contribution risk, highlighting value for uncovering disease-relevant biological features.

Language: Английский

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Obstetric complications and genetic risk for schizophrenia: Differential role of antenatal and perinatal events in first episode psychosis

Acta Psychiatrica Scandinavica, Journal Year: 2023, Volume and Issue: 148(1), P. 81 - 90

Published: March 13, 2023

Abstract Background Obstetric complications (OCs) are key contributors to psychosis risk. However, it is unclear whether they increase vulnerability independently of genetic risk, in interaction with it, or a manifestation proneness. We examined the role distinct types OCs terms risk and tested interact differently vulnerability, whilst accounting for other known environmental factors. Study Design 405 participants (219 first episode patients 186 healthy volunteers) underwent comprehensive assessment OCs, measured using Lewis‐Murray scale divided into pregnancy, abnormalities foetal growth development, delivery. Participants were compared history polygenic score schizophrenia (PRS‐SZ) interactions between these. Results Both pregnancy significantly associated case–control status ( p = 0.02 0.03, respectively), whereas delivery not. PRS‐SZ showed significant association 0.04), but there no either when these considered globally separated based on their timeframe. Conclusions observed obstetric yet may have different impact nature Examining differential might clarify relative contributions this

Language: Английский

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The impact of placental genomic risk for schizophrenia and birth asphyxia on brain development

Translational Psychiatry, Journal Year: 2023, Volume and Issue: 13(1)

Published: Nov. 8, 2023

The placenta plays a role in fetal brain development, and pregnancy birth complications can be signs of placental dysfunction. Birth asphyxia is associated with smaller head size higher risk developing schizophrenia (SZ), but whether genomic factors SZ are related how they might impact development unclear. 433 adult patients 870 healthy controls were clinically evaluated underwent magnetic resonance imaging. Pregnancy information obtained from the Medical Registry Norway. Polygenic scores (PRS) latest genome-wide association study differentiated into PRS (PlacPRS) non-placental PRS. If interaction between PRSs on case-control status was significant, neonatal circumference (nHC) intracranial volume (ICV) further these variables using multiple regression. PlacPRS individuals history likelihood being patient (t = 2.10, p 0.018). We found significant nHC whole sample -2.43, 0.008), for lower those asphyxia. This relationship specific to males -2.71, 0.005) also their ICV -1.97, 0.028). These findings suggest that pathophysiology may affect early late trajectories particularly vulnerability SZ. knowledge lead new strategies treatment prevention

Language: Английский

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Associations between the urban environment and psychotic experiences in adolescents

Schizophrenia Research, Journal Year: 2023, Volume and Issue: 260, P. 123 - 131

Published: Aug. 26, 2023

In 2050 two-thirds of the world's population is predicted to live in cities, which asks for a better understanding how urban environment affects mental health. Urbanicity has repeatedly been found be risk factor, particular psychosis. Here, we explored what factors exposome underlie association between characteristics and psychotic experiences (PE) adolescents.Participants were 815 adolescents (mean age 14.84 years, SD 0.78) from an at-risk cohort (greater Rotterdam area, Netherlands) oversampled on their self-reported emotional behavioral problems. We used linear regression analysis examine with detailed geodata urbanicity (surrounding address density), green space density (high low vegetation), mixed noise levels (road, rail, air, industry, wind power) PE adolescents. Analyses adjusted multiple socio-economic parental confounders. Furthermore, sex-interaction effects.Higher surrounding greenspace each independently associated more (B = 0.18, 95 % CI 0.02; 0.34 B 0.17, 0.01; 0.32, respectively). High only boys 0.23, 0.46). A effect was high -0.46, -0.77; -0.14) -0.49, -0.73; -0.11), illustrating that these associations specific boys.Multiple living area are adolescent boys. Our observations provide leads prevention health problems via designing.

Language: Английский

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