Examining the biological mechanisms of human mental disorders resulting from gene-environment interdependence using novel functional genomic approaches

Silveira, Patrícia Pelufo; Meaney, Michael J.

doi:10.1016/j.nbd.2023.106008

Cited by 11 publications

(5 citation statements)

References 260 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed we found significant main effects of the PRSs of Major depressive disorder 60 and Type 2 diabetes 59 on comorbidity in UK Biobank. Overall, these results align with the well-known capacity of PRS to detect main genetic effects, as well as demonstrate the ability of our ePGS technique in identifying responsivity to environmental change as compared to traditional GWASbased PRS 76 . PRS main effects were not observed in adolescents from ALSPAC probably due to the specificity of the GWAS to the features of the original discovery sample; the majority of GWASs are generated based on adult samples 77 , thus limiting the extrapolation of the effects in different ages.…”

Section: Discussionsupporting

confidence: 82%

Striatal dopamine gene network moderates the effect of early adversity on the risk for adult psychiatric and cardiometabolic comorbidity

Barth

Mar

Filho

et al. 2022

Preprint

View full text Add to dashboard Cite

Psychiatric and cardio-metabolic conditions are commonly comorbid, being a leading cause of disability. Early adversity is a risk factor for both conditions, however, biological pathways remain unknown. The dopamine (DA) system is sensitive to early adversity and influences the development of comorbidities. We hypothesized that early life adversity would functionally link these conditions with the mesocorticolimbic dopamine system as a critical moderator pathway. We computed a co-expression based polygenic score (ePRS) reflecting variations in the function of the dopamine transporter (DAT) gene network in the prefrontal cortex and striatum, the final targets of the mesocorticolimbic pathway. We explored the interaction effects of the ePRS with a score of early life adversity on presence of psychiatric and cardio-metabolic comorbidities in adults (UK Biobank, N= 60016) and adolescents (ALSPAC, N= 910). In adults we also explored genetic and environment effects on gray matter density variations. As predicted, the mesocorticolimbic DAT1 ePRS significantly moderated the impact of early life adversity on the risk for both psychiatric (schizophrenia, neuroticism, mood and substance use disorders) and cardio-metabolic (type 2 diabetes, atherosclerosis, cardiovascular disease) comorbidities in adults and adolescents. Brain gray matter densities in the insula and prefrontal cortex were significantly associated with SNPs from the DAT1 ePRS implicating these regions as critical dopaminergic targets for psychiatric/cardio-metabolic comorbidities. These results reveal that psychiatric and cardio-metabolic comorbidities share common developmental pathways and underlying biological mechanisms.

show abstract

Section: Discussionsupporting

confidence: 82%

Striatal dopamine gene network moderates the effect of early adversity on the risk for adult psychiatric and cardiometabolic comorbidity

Barth

Mar

Filho

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The ePRS-IR aggregates information on the relationship between the gene of interest and other genes in the genome, the levels of tissue-specific gene expression, the genetic variation of the target sample (given by the genotyping data) and the tissue-specific effect size of the association between genotyping and gene expression (given by GTeX). Therefore, variations in the ePRS-IR represent individual variations in the expression of the tissuespecific gene co-expression network [18]. In the case of our study, variations in the ePRS-IR represent individual variations in the expression of the insulin receptor gene network in the mesocorticolimbic area or in the hippocampus.…”

Section: Introductionmentioning

confidence: 78%

Biologically Informed Polygenic Scores for Brain Insulin Receptor Network Are Associated with Cardiometabolic Risk Markers and Diabetes in Women

Selenius,

Silveira,

Bonsdorff

et al. 2024

Diabetes Metab J

View full text Add to dashboard Cite

Highlights • ePRSs, based on co-expression, reflect tissue-specific biological functions. • ePRSs associated with the insulin receptor gene network are linked to type 2 diabetes. • Corresponding links were with adverse lipid profiles and body composition. • These associations were seen in the hippocampal area, exclusively among older women. • The brain insulin receptor gene network appears to influence cardiometabolic risk.

show abstract

“…This difference would be expected if SNP’s comprising an ePGS are context dependent. This may explain why the ePGS may be more suited to identify GxE interaction effects 40 as documented below.…”

Section: Resultsmentioning

confidence: 99%

Expression based polygenic scores - A gene network perspective to capture individual differences in biological processes

Barth,

de Mendonça Filho,

Arcego

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Incorporating functional aspects into polygenic scores may accelerate early diagnosis and the discovery of therapeutic targets. Yet, existing polygenic scores summarize information from genome wide statistical associations between SNPs and phenotypes. We developed the novel biologically informed, expression-based polygenic scores (ePRS or ePGS). The method characterizes tissue specific gene co-expression networks from genome-wide RNA sequencing data and incorporates this information into polygenic scores. Performance and characteristics of the ePGS were compared to traditional polygenic risk score (PRS). We observed that ePGS differs from PRS for aggregating information on; i. the relation between different genes (co-expression); ii. the levels of tissue-specific gene expression; iii. the genetic variation of the target sample; iv. the tissue-specific effect size of the association between genotyping and gene expression; v. the portability across different ancestries. Variations in the ePGS represent individual variations in the expression of a tissue-specific gene co-expression network, and this methodology may profoundly influence the way we study human disease biology.

show abstract

Examining the biological mechanisms of human mental disorders resulting from gene-environment interdependence using novel functional genomic approaches

Cited by 11 publications

References 260 publications

Striatal dopamine gene network moderates the effect of early adversity on the risk for adult psychiatric and cardiometabolic comorbidity

Striatal dopamine gene network moderates the effect of early adversity on the risk for adult psychiatric and cardiometabolic comorbidity

Biologically Informed Polygenic Scores for Brain Insulin Receptor Network Are Associated with Cardiometabolic Risk Markers and Diabetes in Women

Expression based polygenic scores - A gene network perspective to capture individual differences in biological processes

Contact Info

Product

Resources

About