Progress and Challenges in GxE Research on Depression

Belsky, Daniel W.; Domingue, Benjamin W.

doi:10.1176/appi.ajp.20221039

Cited by 4 publications

(4 citation statements)

References 18 publications

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“…Though further research is certainly needed to evaluate these practical implications, this is synchronous with calls to address social determinants of opioid (mis) use (Dasgupta et al, 2018) in part through early intervention in adverse environments. Evidence suggests that environmental/social adversity may moderate genetic influences on both internalizing and externalizing behavior (Belsky & Domingue, 2023;Dash, Karalunas, et al, 2023); if genetic influences on psychopathology overlap with opioid use behaviors, such environmental interventions may also serve to attenuate liability to opioid use at the population level over time. As such, an important next step will be to examine how environmental influences such as social adversity and drug availability may moderate genetic risk for heroin use and POM.…”

Section: Aabmentioning

confidence: 99%

Differential etiologic associations of heroin use and prescription opioid misuse with psychopathology.

Dash,

Gizer,

Martin

et al. 2024

Journal of Psychopathology and Clinical Science

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Patterns of association with externalizing and internalizing features differ across heroin use and prescription opioid misuse (POM). The present study examined whether heroin use and POM display differential etiologic overlap with symptoms of conduct disorder (CD), adult antisocial behavior (AAB), and major depressive episodes (MDEs), how aggregating heroin use and POM into a single phenotype may bias results, and explored potential sex differences. Seven thousand one hundred and sixty-four individual twins from the Australian Twin Registry (ATR; 59.81% female; M age = 30.58 years) reported lifetime heroin use, POM, CD symptoms, AABs, and MDE symptoms within a semi-structured interview. Biometric models decomposed phenotypic variance and covariance into additive genetic, common environmental, and unique environmental effects. The proportion of variance in heroin use attributable to factors shared with CD, AAB, and MDE, respectively, was 41%, 41%, and 0% for men and 26%, 19%, and 42% for women; for POM, the proportions were 33%, 35%, and 20% for men and 15%, 9%, and 13% for women. CD and AAB were more strongly genetically correlated with heroin use among women and with POM among men. MDE was more strongly genetically correlated with POM than with heroin use among men, but more strongly genetically correlated with heroin use than with POM among women. Analyses using an aggregate opioid (mis)use variable were biased toward POM, which was the more prevalent phenotype. Magnitude and source of etiologic influence may differ across forms of opioid (mis)use and sex. Disaggregating heroin use and POM in future opioid research may be warranted.

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Section: Aabmentioning

confidence: 99%

Differential etiologic associations of heroin use and prescription opioid misuse with psychopathology.

Dash,

Gizer,

Martin

et al. 2024

Journal of Psychopathology and Clinical Science

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“…Because European ancestry GWAS are not equally predictive when applied to non-European populations, GWAS-derived PRS perform suboptimally in non-European populations (Belsky & Domingue, 2023;Martin et al, 2019;Peterson et al, 2019;Wray et al, 2021). This presents a significant challenge in conducting research with individuals of non-European ancestral backgrounds and is contributing to the perpetuation of underrepresentation of non-White individuals in research (Popejoy & Fullerton, 2016).…”

Section: Child Maltreatment and Genetic Influencesmentioning

confidence: 99%

“…Additionally, because the majority of G×E studies have been conducted using samples of European ancestry, there is a critical need for greater representation of diverse individuals in G×E research (Peterson et al., 2019). Finally, polygenic scores that consider multiple genes simultaneously have become increasingly widespread given the increased awareness of limitations described above and the recognition that most outcomes are highly polygenic (Belsky & Domingue, 2023; Boyle et al., 2017; Visscher et al., 2008).…”

Section: Introductionmentioning

confidence: 99%

A person‐centered data analytic approach to dopaminergic polygenic moderation of child maltreatment exposure

Handley

Russotti

Ross

et al. 2023

Developmental Psychobiology

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The present study illustrates the utility of latent class analysis, a person-centered data analytic approach, as an innovative method for identifying naturally occurring patterns of polygenic risk, specifically within the dopaminergic system. Moreover, this study tests whether latent classes of polygenic variation moderate the effect of child maltreatment exposure on internalizing symptoms among African ancestry youth.African ancestry youth were selected for this study because youth of color are overrepresented in the child welfare system and because African ancestry individuals are significantly underrepresented in genomics research. Results identified three latent classes of dopaminergic gene variation. Class 1 was marked predominately by homozygous minor alleles, Class 2 was characterized by homozygous major and heterozygous presentations, and Class 3 was marked by heterozygous alleles on the DAT-1 singlenucleotide polymorphisms (SNPs) and a combination of homozygous major and minor alleles on the other SNPs. Results indicated that a greater number of maltreatment subtypes experienced were associated with higher internalizing symptoms only for children with the latent polygenic Class 2 pattern. This latent class was distinctly characterized by more homozygous major or heterozygous allelic presentations along all three DAT-1 SNPs. This significant latent polygenic class by environment interaction was replicated in an independent replication sample. Together, findings suggest that African ancestry children with a pattern of dopaminergic variation characterized by this specific combination of polygenic variation are more vulnerable to developing internalizing symptoms following maltreatment exposure, relative to their peers with other dopamine-related polygenic patterns.

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“…However, the reliability of these and other candidate-gene-based findings has been challenged by recent GWAS results ( 18–20 ). Recent work has advocated the use of PRS derived from large-scale GWAS for investigating gene–environment interplay in psychiatric disorders ( 21 ). In addition, environmental factors are complex to measure and interdependent, and previous work has focused only on one or few factors per study ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

Gut microbial diversity moderates polygenic risk of schizophrenia

Zhang,

Yuan,

et al. 2024

Front. Psychiatry

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BackgroundSchizophrenia (SCZ) is a heritable disorder with a polygenic architecture, and the gut microbiota seems to be involved in its development and outcome. In this study, we investigate the interplay between genetic risk and gut microbial markers.MethodsWe included 159 first-episode, drug-naïve SCZ patients and 86 healthy controls. The microbial composition of feces was characterized using the 16S rRNA sequencing platform, and five microbial α-diversity indices were estimated [Shannon, Simpson, Chao1, the Abundance-based Eoverage Estimator (ACE), and a phylogenetic diversity-based estimate (PD)]. Polygenic risk scores (PRS) for SCZ were constructed using data from large-scale genome-wide association studies. Effects of microbial α-diversity, microbial abundance, and PRS on SCZ were evaluated via generalized linear models.ResultsWe confirmed that PRS was associated with SCZ (OR = 2.08, p = 1.22×10−5) and that scores on the Shannon (OR = 0.29, p = 1.15×10−8) and Simpson (OR = 0.29, p = 1.25×10−8) indices were inversely associated with SCZ risk. We found significant interactions (p < 0.05) between PRS and α-diversity indices (Shannon, Simpson, and PD), with the effects of PRS being larger in those exhibiting higher diversity compared to those with lower diversity. Moreover, the PRS effects were larger in individuals with a high abundance of the genera Romboutsia, Streptococcus, and Anaerostipes than in those with low abundance (p < 0.05). All three of these genera showed protective effects against SCZ.ConclusionThe current findings suggest an interplay between the gut microbiota and polygenic risk of SCZ that warrants replication in independent samples. Experimental studies are needed to determine the underpinning mechanisms.

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Progress and Challenges in GxE Research on Depression

Cited by 4 publications

References 18 publications

Differential etiologic associations of heroin use and prescription opioid misuse with psychopathology.

Differential etiologic associations of heroin use and prescription opioid misuse with psychopathology.

A person‐centered data analytic approach to dopaminergic polygenic moderation of child maltreatment exposure

Gut microbial diversity moderates polygenic risk of schizophrenia

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