Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling.

We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.

The joint effects of genetic liability and the death of close relatives on risk for major depression and alcohol use disorder in a Swedish national sample.

BACKGROUND: To determine whether genetic risk factors for major depression (MD) and alcohol use disorder (AUD) interact with a potent stressor - death of spouse, parent, and sibling - in predicting episodes of, respectively, MD and AUD. METHODS: MD and AUD registrations were assessed from national Swedish registries. In individuals born in Sweden 1960-1970, we identified 7586, 388 459, and 34 370 with the loss of, respectively, a spouse, parent, and sibling. We started following subjects at age 18 or the year 2002 with end of follow-up in 2018. We examined time to event - a registration for MD within 6 months or AUD within a year - on an additive scale, using the Nelson-Aalen estimator. Genetic risk was assessed by the Family Genetic Risk Score (FGRS). RESULTS: In separate models controlling for the main effects of death of spouse, parent, and sibling, FGRS, and sex, significant interactions were seen in all analyses between genetic risk for MD and death of relative in prediction of subsequent MD registration. A similar pattern of results, albeit with weaker interaction effects, was seen for genetic risk for AUD and risk for AUD registration. Genetic risk for bipolar disorder (BD) and anxiety disorders (AD) also interacted with event exposure in predicting MD. CONCLUSIONS: Genetic risk for both MD and AUD act in part by increasing the sensitivity of individuals to the pathogenic effects of environmental stressors. For prediction of MD, similar effects are also seen for genetic risk for AD and BD.

BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos.

Carriers of heterozygous germline BAP1 mutations (BAP1+/-) are affected by the "BAP1 cancer syndrome." Although they can develop almost any cancer type, they are unusually susceptible to asbestos carcinogenesis and mesothelioma. Here we investigate why among all carcinogens, BAP1 mutations cooperate with asbestos. Asbestos carcinogenesis and mesothelioma have been linked to a chronic inflammatory process promoted by the extracellular release of the high-mobility group box 1 protein (HMGB1). We report that BAP1+/- cells secrete increased amounts of HMGB1, and that BAP1+/- carriers have detectable serum levels of acetylated HMGB1 that further increase when they develop mesothelioma. We linked these findings to our discovery that BAP1 forms a trimeric protein complex with HMGB1 and with histone deacetylase 1 (HDAC1) that modulates HMGB1 acetylation and its release. Reduced BAP1 levels caused increased ubiquitylation and degradation of HDAC1, leading to increased acetylation of HMGB1 and its active secretion that in turn promoted mesothelial cell transformation.

DNA methylome analysis provides insights into gene regulatory mechanism for better performance of rice under fluctuating environmental conditions: epigenomics of adaptive plasticity.

MAIN CONCLUSION: Roots play an important role in adaptive plasticity of rice under dry/direct-sown conditions. However, hypomethylation of genes in leaves (resulting in up-regulated expression) complements the adaptive plasticity of Nagina-22 under DSR conditions. Rice is generally cultivated by transplanting which requires plenty of water for irrigation. Such a practice makes rice cultivation a challenging task under global climate change and reducing water availability. However, dry-seeded/direct-sown rice (DSR) has emerged as a resource-saving alternative to transplanted rice (TPR). Though some of the well-adapted local cultivars are used for DSR, only limited success has been achieved in developing DSR varieties mainly because of a limited knowledge of adaptability of rice under fluctuating environmental conditions. Based on better morpho-physiological and agronomic performance of Nagina-22 (N-22) under DSR conditions, N-22 and IR-64 were grown by transplanting and direct-sowing and used for whole genome methylome analysis to unravel the epigenetic basis of adaptive plasticity of rice. Comparative methylome and transcriptome analyses indicated a large number (4078) of genes regulated through DNA methylation/demethylation in N-22 under DSR conditions. Gene × environment interactions play important roles in adaptive plasticity of rice under direct-sown conditions. While genes for pectinesterase, LRK10, C2H2 zinc-finger protein, splicing factor, transposable elements, and some of the unannotated proteins were hypermethylated, the genes for regulation of transcription, protein phosphorylation, etc. were hypomethylated in CG context in the root of N-22, which played important roles in providing adaptive plasticity to N-22 under DSR conditions. Hypomethylation leading to up-regulation of gene expression in the leaf complements the adaptive plasticity of N-22 under DSR conditions. Moreover, differential post-translational modification of proteins and chromatin assembly/disassembly through DNA methylation in CHG context modulate adaptive plasticity of N-22. These findings would help developing DSR cultivars for increased water-productivity and ecological efficiency.

Genome-wide association studies revealed complex genetic architecture and breeding perspective of maize ear traits.

BACKGROUND: Maize (Zea Mays) is one of the world's most important crops. Hybrid maize lines resulted a major improvement in corn production in the previous and current centuries. Understanding the genetic mechanisms of the corn production associated traits greatly facilitate the development of superior hybrid varieties. RESULT: In this study, four ear traits associated with corn production of Nested Association Mapping (NAM) population were analyzed using a full genetic model, and further, optimal genotype combinations and total genetic effects of current best lines, superior lines, and superior hybrids were predicted for each of the traits at four different locations. The analysis identified 21-34 highly significant SNPs (-log10P > 5), with an estimated total heritability of 37.31-62.34%, while large contributions to variations was due to dominance, dominance-related epistasis, and environmental interaction effects ([Formula: see text] 14.06% ~ 49.28%), indicating these factors contributed significantly to phenotypic variations of the ear traits. Environment-specific genetic effects were also discovered to be crucial for maize ear traits. There were four SNPs found for three ear traits: two for ear length and weight, and two for ear row number and length. Using the Enumeration method and the stepwise tuning technique, optimum multi-locus genotype combinations for superior lines were identified based on the information obtained from GWAS. CONCLUSIONS: Predictions of genetic breeding values showed that different genotype combinations in different geographical regions may be better, and hybrid-line variety breeding with homozygote and heterozygote genotype combinations may have a greater potential to improve ear traits.

Cascading indirect genetic effects in a clonal vertebrate.

Understanding how individual differences arise and how their effects propagate through groups are fundamental issues in biology. Individual differences can arise from indirect genetic effects (IGE): genetically based variation in the conspecifics with which an individual interacts. Using a clonal species, the Amazon molly (Poecilia formosa), we test the hypothesis that IGE can propagate to influence phenotypes of the individuals that do not experience them firsthand. We tested this by exposing genetically identical Amazon mollies to conspecific social partners of different clonal lineages, and then moving these focal individuals to new social groups in which they were the only member to have experienced the IGE. We found that genetically different social environments resulted in the focal animals experiencing different levels of aggression, and that these IGE carried over into new social groups to influence the behaviour of naive individuals. These data reveal that IGE can cascade beyond the individuals that experience them. Opportunity for cascading IGE is ubiquitous, especially in species with long-distance dispersal or fission-fusion group dynamics. Cascades could amplify (or mitigate) the effects of IGE on trait variation and on evolutionary trajectories. Expansion of the IGE framework to include cascading and other types of carry-over effects will therefore improve understanding of individual variation and social evolution and allow more accurate prediction of population response to changing environments.

Modeling Interaction and Dispersion Effects in the Analysis of Gene-by-Environment Interaction.

Genotype-by-environment interaction (GxE) studies probe heterogeneity in response to risk factors or interventions. Popular methods for estimation of GxE examine multiplicative interactions between individual genetic and environmental measures. However, risk factors and interventions may modulate the total variance of an epidemiological outcome that itself represents the aggregation of many other etiological components. We expand the traditional GxE model to directly model genetic and environmental moderation of the dispersion of the outcome. We derive a test statistic, [Formula: see text], for inferring whether an interaction identified between individual genetic and environmental measures represents a more general pattern of moderation of the total variance in the phenotype by either the genetic or the environmental measure. We validate our method via extensive simulation, and apply it to investigate genotype-by-birth year interactions for Body Mass Index (BMI) with polygenic scores in the Health and Retirement Study (N = 11,586) and individual genetic variants in the UK Biobank (N = 380,605). We find that changes in the penetrance of a genome-wide polygenic score for BMI across birth year are partly representative of a more general pattern of expanding BMI variation across generations. Three individual variants found to be more strongly associated with BMI among later born individuals, were also associated with the magnitude of variability in BMI itself within any given birth year, suggesting that they may confer general sensitivity of BMI to a range of unmeasured factors beyond those captured by birth year. We introduce an expanded GxE regression model that explicitly models genetic and environmental moderation of the dispersion of the outcome under study. This approach can determine whether GxE interactions identified are specific to the measured predictors or represent a more general pattern of moderation of the total variance in the outcome by the genetic and environmental measures.

"Reports of My Death Were Greatly Exaggerated": Behavior Genetics in the Postgenomic Era.

Behavior genetics studies how genetic differences among people contribute to differences in their psychology and behavior. Here, I describe how the conclusions and methods of behavior genetics have evolved in the postgenomic era in which the human genome can be directly measured. First, I revisit the first law of behavioral genetics stating that everything is heritable, and I describe results from large-scale meta-analyses of twin data and new methods for estimating heritability using measured DNA. Second, I describe new methods in statistical genetics, including genome-wide association studies and polygenic score analyses. Third, I describe the next generation of work on gene × environment interaction, with a particular focus on how genetic influences vary across sociopolitical contexts and exogenous environments. Genomic technology has ushered in a golden age of new tools to address enduring questions about how genes and environments combine to create unique human lives.

On the deformability of an empirical fitness landscape by microbial evolution.

A fitness landscape is a map between the genotype and its reproductive success in a given environment. The topography of fitness landscapes largely governs adaptive dynamics, constraining evolutionary trajectories and the predictability of evolution. Theory suggests that this topography can be deformed by mutations that produce substantial changes to the environment. Despite its importance, the deformability of fitness landscapes has not been systematically studied beyond abstract models, and little is known about its reach and consequences in empirical systems. Here we have systematically characterized the deformability of the genome-wide metabolic fitness landscape of the bacterium Escherichia coli Deformability is quantified by the noncommutativity of epistatic interactions, which we experimentally demonstrate in mutant strains on the path to an evolutionary innovation. Our analysis shows that the deformation of fitness landscapes by metabolic mutations rarely affects evolutionary trajectories in the short range. However, mutations with large environmental effects produce long-range landscape deformations in distant regions of the genotype space that affect the fitness of later descendants. Our results therefore suggest that, even in situations in which mutations have strong environmental effects, fitness landscapes may retain their power to forecast evolution over small mutational distances despite the potential attenuation of that power over longer evolutionary trajectories. Our methods and results provide an avenue for integrating adaptive and eco-evolutionary dynamics with complex genetics and genomics.

Epigenetics, Development, and Psychopathology.

Epigenetic mechanisms govern the transcription of the genome. Research with model systems reveals that environmental conditions can directly influence epigenetic mechanisms that are associated with interindividual differences in gene expression in brain and neural function. In this review, we provide a brief overview of epigenetic mechanisms and research with relevant rodent models. We emphasize more recent translational research programs in epigenetics as well as the challenges inherent in the integration of epigenetics into developmental and clinical psychology. Our objectives are to present an update with respect to the translational relevance of epigenetics for the study of psychopathology and to consider the state of current research with respect to its potential importance for clinical research and practice in mental health.

Disentangling genes, attachment, and environment: A systematic review of the developmental psychopathology literature on gene-environment interactions and attachment.

The role of genetics in relation to attachment is of continued interest to developmental psychology. Recent research has attempted to disentangle genetic main effects, environmental effects, and gene and environment (G × E) interactions in the development of attachment security/insecurity and disorganization. We systematically reviewed associations between gene markers and attachment, including G × E interactions, identifying 27 eligible studies. Inconsistent results emerged for associations between both gene effects and G × E interactions on attachment organization. Where G × E interactions used attachment as the environmental factor in the interaction, we observed more consistent results for differential susceptibility of G × E interactions on offspring behavior. Small sample size and heterogeneity in measurement of environmental factors impacted on comparability of studies. From these results, we propose that the future of research into the role of genetic effects in attachment lies in further exploration of G × E interactions, particularly where attachment acts as an environmental factor impacting on other child developmental outcomes emerging from the caregiving environment, consistent with differential susceptibility approaches to developmental psychopathology. In addition, from a methodological perspective, establishing the role of gene markers in such models will require a shift toward contemporary genomics, including genome-wide analysis (including novel genes and chromosomal loci), and epigenetic individual variations.

Power and Sample Size Calculations for Genetic Association Studies in the Presence of Genetic Model Misspecification.

INTRODUCTION: When analyzing data from large-scale genetic association studies, such as targeted or genome-wide resequencing studies, it is common to assume a single genetic model, such as dominant or additive, for all tests of association between a given genetic variant and the phenotype. However, for many variants, the chosen model will result in poor model fit and may lack statistical power due to model misspecification. OBJECTIVE: We develop power and sample size calculations for tests of gene and gene × environment interaction, allowing for misspecification of the true mode of genetic susceptibility. METHODS: The power calculations are based on a likelihood ratio test framework and are implemented in an open-source R package ("genpwr"). RESULTS: We use these methods to develop an analysis plan for a resequencing study in idiopathic pulmonary fibrosis and show that using a 2-degree of freedom test can increase power to detect recessive genetic effects while maintaining power to detect dominant and additive effects. CONCLUSIONS: Understanding the impact of model misspecification can aid in study design and developing analysis plans that maximize power to detect a range of true underlying genetic effects. In particular, these calculations help identify when a multiple degree of freedom test or other robust test of association may be advantageous.

Rice quality: How is it defined by consumers, industry, food scientists, and geneticists?

BACKGROUND: Quality is a powerful engine in rice value chain upgrading. However, there is no consensus on how "rice quality" should be defined and measured in the rice sector. SCOPE AND APPROACH: We adopt a Lancasterian definition of rice quality as a bundle of intrinsic and extrinsic attributes. We then review how rice quality is (i) perceived and defined by consumers and industry stakeholders in rice value chains in Southeast and South Asia; (ii) measured and defined by food technologists; and (iii) predicted through genetics. KEY FINDINGS AND CONCLUSIONS: Consumers are heterogeneous with respect to their perceived differentiation of rice quality among regions, countries, cities, and urbanization levels. Premium quality is defined by nutritional benefits, softness and aroma in Southeast Asia, and by the physical appearance of the grains (uniformity, whiteness, slenderness), satiety, and aroma in South Asia. These trends are found to be consistent with industry perceptions and have important implications for regional and national breeding programs in terms of tailoring germplasm to regions and rice varieties to specific local market segments. Because rice is traded internationally, there is a need to standardize definitions of rice quality. However, food technologists have not reached unanimity on quality classes and measurement; routine indicators need to be complemented by descriptive profiles elicited through sensory evaluation panels. Finally, because rice quality is controlled by multiple interacting genes expressed through environmental conditions, predicting grain quality requires associating genetic information with grain quality phenotypes in different environments.

Anxiety and exploratory behavior in the African striped mouse, Rhabdomys, taxa are partially modified by the physical rearing environment.

The environment may modulate genetic influences on behavioral expression. We investigated whether the physical rearing environment modulates anxiety and exploratory behavior in four populations, representing three species, of the striped mouse Rhabdomys. One population originated from an arid, open habitat and the others from grassy, covered habitats, and two species occurred in sympatry. We raised captive individuals of all populations in treatments that simulated cover or no cover for two generations and investigated the behavior of resulting adults in an open-field, light-dark and startle response tests. We expected that, when raised without cover, the arid population would be less anxious and more exploratory than grassland populations, but found the opposite in the open-field test only. We also expected that all individuals would be anxious and less exploratory when raised under cover, which was the case for anxiety in a light-dark test, but individuals from the no cover treatment were more anxious in the open-field test. Only one population × treatment interaction was detected in which the arid population was least exploratory. Therefore, the physical rearing environment had less of an influence than phylogeny on the development of anxiety and exploration in Rhabdomys.

Prenatal Stress, Maternal Immune Dysregulation, and Their Association With Autism Spectrum Disorders.

PURPOSE OF REVIEW: While genetic factors are a major etiological contributor to autism spectrum disorder (ASD), evidence also supports a role for environmental factors. Herein, we will discuss two such factors that have been associated with a significant proportion of ASD risk: prenatal stress exposure and maternal immune dysregulation, and how sex and gender relate to these factors. RECENT FINDINGS: Recent evidence suggests that maternal stress susceptibility interacts with prenatal stress exposure to affect offspring neurodevelopment. Additionally, understanding of the impact of maternal immune dysfunction on ASD has recently been advanced by recognition of specific fetal brain proteins targeted by maternal autoantibodies, and identification of unique mid-gestational maternal immune profiles. Animal models have been developed to explore pathophysiology targeting both of these factors, with limited sex-specific effects observed. While prenatal stress and maternal immune dysregulation are associated with ASD, most cases of these prenatal exposures do not result in ASD, suggesting interaction with multiple other risks. We are beginning to understand the behavioral, pharmacopathological, and epigenetic effects related to these interactions, as well as potential mitigating factors. Sex differences of these risks have been understudied but are crucial for understanding the higher prevalence of ASD in boys. Continued growth in understanding of these mechanisms may ultimately allow for the identification of multiple potential points for prevention or intervention, and for a personalized medicine approach for this subset of environmental-associated ASD cases.

Perceived Family Cohesion Moderates Environmental Influences on Prosocial Behavior in Nigerian Adolescent Twins.

Research shows that perceived family cohesion is positively related to prosocial behavior in adolescents. In this study, we investigated heritability of prosocial behavior (PB) and perceived family cohesion (FC) among Nigerian twins attending public schools in Lagos State, Nigeria (mean age = 14.7 years, SD = 1.7 years), and explored the issue of whether children's perception of cohesive family environment moderated genetic and environmental influences on (PB). The PB scale of the Strengths and Difficulties Questionnaire and the FC scale of the Family Adaptability and Cohesion Evaluation Scale III were completed by 2,376 twins (241 monozygotic (MZ) male, 354 MZ female, 440 dizygotic (DZ) male, 553 DZ female, and 788 opposite-sex DZ twins). A general sex-limitation and the bivariate genotype by environment interaction (G×E) models were applied to the data. The general sex-limitation model showed no significant sex differences, indicating that additive genetic and non-shared environmental influences were, 38% (95% CI = 31, 46) and 62% (95% CI = 54, 69) for PB and 33% (95% CI = 24, 40) and 67% (95% CI = 60, 76) for FC in both sexes. These estimates were similar to those found in Western and Asian twin studies to date. The correlation between PB and FC was 0.36. The best-fitting bivariate G×E model indicated that FC significantly moderated non-shared environmental influence unique to PB (E×E interaction). Specifically, non-shared environmental contributions to PB were highest when FC was lowest, and decreased as the levels of FC increased. However, genetic variances in PB were stable across all levels of FC. These findings suggest that FC reduces individual differences in PB by changing non-shared environmental experiences rather than genetic factors in PB.

Applying Novel Methods for Assessing Individual- and Neighborhood-Level Social and Psychosocial Environment Interactions with Genetic Factors in the Prediction of Depressive Symptoms in the Multi-Ethnic Study of Atherosclerosis.

Complex illnesses, like depression, are thought to arise from the interplay between psychosocial stressors and genetic predispositions. Approaches that take into account both personal and neighborhood factors and that consider gene regions as well as individual SNPs may be necessary to capture these interactions across race and ethnic groups. We used novel gene-region based analysis methods [Sequence Kernel Association Test (SKAT) and meta-analysis (MetaSKAT), gene-environment set association test (GESAT)], as well as traditional linear models to identify gene region and SNP × psychosocial factor interactions at the individual- and neighborhood-level, across multiple race/ethnicities. Multiple regions identified in SKAT analyses showed evidence of a significant gene-region association with averaged depressive symptom scores across race/ethnicity (MetaSKAT p values <0.001). One region × neighborhood-environment interaction was significantly associated with averaged depressive symptom score across race/ethnicity after multiple testing correction (chr 18:21454070-21494070, Fisher's combined p value = 0.001). The examination of gene regions jointly with environmental factors measured at multiple levels (individuals and their contexts) may shed light on the etiology of depressive illness across race/ethnicities.

A functional variant in the neuropeptide S receptor 1 gene moderates the influence of urban upbringing on stress processing in the amygdala.

We have previously shown that urban upbringing and city living were associated with stress-induced activity in the amygdala and the perigenual anterior cingulate cortex (pACC). This finding might link the epidemiological risk factor "urbanicity" to neurobiological mechanisms of psychiatric disorders. However, given the heritability of stress-related phenotypes, it appears likely that genetic factors can modulate the effect of urbanicity on social stress processing. In the present exploratory study, we investigated if a functional sequence variation in the neuropeptide S receptor gene (NPSR1 rs324981) is associated with brain activation patterns under acute psychosocial stress and if it modulates the link between urbanicity and central stress processing. In animals, neuropeptide S has strong anxiolytic effects and it induces hypothalamus-pituitary-adrenal (HPA) axis activation. In humans, rs324981 was found to be associated with anxiety and stress-related phenotypes. Forty-two subjects were exposed to a psychosocial stress task for scanner environments (ScanSTRESS). While no main effect of rs324981 on amygdala and pACC activity was detected, we found a distinct interaction between rs324981 and urban upbringing modulating right amygdala responses. Moreover, right amygdala responses were significantly higher in subjects who also showed a salivary cortisol response to the stress exposure. The present finding of a gene × environment interaction further supports the view that the brain NPS system is involved in central stress regulation. This study provides first evidence for the assumption that a NPSR1 variant modulates brain activation under stress, interacting with the environmental risk factor urban upbringing.

Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype and stressful life events interact to predict preschool-onset depression: a replication and developmental extension.

BACKGROUND: Scientific enthusiasm about gene × environment interactions, spurred by the 5-HTTLPR (serotonin transporter-linked polymorphic region) × SLEs (stressful life events) interaction predicting depression, have recently been tempered by sober realizations of small effects and meta-analyses reaching opposing conclusions. These mixed findings highlight the need for further research. Converging evidence suggests that the effects of 5-HTTLPR genotype may be neurodevelopmental in origin, but we are not aware of empirical studies that have investigated whether the 5-HTTLPR genotype × SLE interaction predicts preschool-onset depression (PO-MDD), the earliest validated form of depression. METHODS: Children (n = 234) aged 3-5 were recruited for a longitudinal study designed to examine PO-MDD. In a comprehensive baseline assessment, the child's primary caregivers completed questionnaires and were interviewed about their child's behaviors, psychiatric symptoms, and exposure to SLEs. RESULTS: A 5-HTTLPR × SLEs interaction emerged, such that children homozygous for the short allele were more susceptible to depression in the context of elevated SLE than long allele carriers. In contrast, at low SLE exposure, short allele homozygotes had fewer depressive symptoms. The data were best fit by a plasticity model with a substantial reduction in fit by diathesis-stress models. CONCLUSIONS: Extending studies in adult and adolescent populations, these data suggest that 5-HTTLPR genotype may provide plasticity to environmental influence, for better or worse. Specifically, children homozygous for the short allele were more susceptible to the depressogenic effects of SLEs but benefitted, in the form of reduced depressive symptoms, in the context of relatively benign environmental conditions (i.e. relatively low SLE exposure). These data highlight the importance of examining gene × environment interactions across development, environment, and outcome but should be interpreted cautiously given the small sample size.

Interactions of the CSF3R polymorphism and early stress on future orientation: evidence for the differential model of stress-related growth.

AIMS: This study aims to explore the concept of future orientation, which encompasses individuals' thoughts about the future, goal-setting, planning, response to challenges and behavioural adjustments in evolving situations. Often viewed as a psychological resource, future orientation is believed to be developed from psychological resilience. The study investigates the curvilinear relationship between childhood maltreatment and future orientation while examining the moderating effects of genotype. METHODS: A total of 14,675 Chinese adults self-reported their experiences of childhood maltreatment and their future orientation. The influence of genetic polymorphism was evaluated through genome-wide interaction studies (GWIS; genome-wide association study [GWAS] using gene × environment interaction) and a candidate genes approach. RESULTS: Both GWAS and candidate genes analyses consistently indicated that rs4498771 and its linked single-nucleotide polymorphisms, located in the intergenic area surrounding CSF3R, significantly interacted with early trauma to influence future orientation. Nonlinear regression analyses identified a quadratic or cubic association between future orientation and childhood maltreatment across some genotypes. Specifically, as levels of childhood maltreatment increased, future orientation declined for all genotypes. However, upon reaching a certain threshold, future orientation exhibited a rebound in individuals with specific genotypes. CONCLUSIONS: The findings suggest that individuals with certain genotypes exhibit greater resilience to childhood maltreatment. Based on these results, we propose a new threshold model of stress-related growth.