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While genetic factors, behavior, and environmental exposures form a complex web of interrelated associations in type 2 diabetes (T2D), their interaction is poorly understood. Here, using data from ~500K participants of the UK Biobank, we identify the genetic determinants of a "polyexposure risk score" (PXS) a new risk factor that consists of an accumulation of 25 associated individual-level behaviors and environmental risk factors that predict longitudinal T2D incidence. PXS-T2D had a non-zero heritability (h2 = 0.18) extensive shared genetic architecture with established clinical and biological determinants of T2D, most prominently with body mass index (genetic correlation [rg] = 0.57) and Homeostatic Model Assessment for Insulin Resistance (rg = 0.51). Genetic loci associated with PXS-T2D were enriched for expression in the brain. Biobank scale data with genetic information illuminates how complex and cumulative exposures and behaviors as a whole impact T2D risk but whose biology have been elusive in genome-wide studies of T2D.

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BACKGROUND: Although genetic and environmental factors are involved in the aetiology of bipolar disorder [BD], studies focused on their interplay are lacking. The current investigation examines interactions and correlations between polygenic risk scores [PRS] for BD and major depressive disorder [MDD] with stressful life events [SLEs] in liability for BD. METHODS: This study used data from 1715 participants (862 bipolar cases and 853 controls) taken from UK and Canadian samples. The List of Threatening Experiences Questionnaire recorded SLEs that occurred 6 months before interview for controls and 6 months prior to the first (Canadian sample) and worst (UK sample) depressive and manic episodes for bipolar cases. PRS-BD and PRS-MDD were calculated from the Psychiatric Genomics Consortium. RESULTS: For the worst depressive episode, the PRS-MDD was significantly correlated with total number of SLEs (ß = 0.13, 95 % CI:0.04-0.22, p = 0.003) and dependent SLEs (ß = 0.09, 95 % CI:0.02-0.16, p = 0.007). After correction for multiple testing nominally significant correlations were detected for PRS-BD with total number of SLEs (ß = 0.11, 95 % CI:0.02-0.20, p = 0.015) and dependent SLEs (ß = 0.08, 95 % CI:0.01-0.15, p = 0.019). Among bipolar cases, these associations were slightly stronger but were only of nominal significance for total number of SLEs (PRS-MDD: ß = 0.19, 95 % CI:0.04-0.35, p = 0.015; PRS-BD: ß = 0.16, 95 % CI:0.01-0.32, p = 0.042) and dependent SLEs (PRS-MDD: ß = 0.14, 95 % CI:0.03-0.26, p = 0.015; PRS-BD: ß = 0.12, 95 % CI:0.004-0.24, p = 0.043). No other significant gene-environment correlations or interactions were found. LIMITATIONS: Use of a larger sample size would be beneficial. CONCLUSIONS: The relationship between SLEs and genetic risk for mood disorders may be best explained through correlations rather than interactions.

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OBJECTIVES: The educational gradient in late-life health is well established. Despite this, there are still ambiguities concerning the role of underlying confounding by genetic influences and gene-environment (GE) interplay. Here, we investigate the role of educational factors (attained and genetic propensities) on health and mortality in late life using genetic propensity for educational attainment (as measured by a genome-wide polygenic score, PGSEdu) and attained education. METHODS: By utilizing genetically informative twin data from the Swedish Twin Registry (n = 14,570), we investigated influences of the educational measures, familial confounding as well as the possible presence of passive GE correlation on both objective and subjective indicators of late-life health, that is, the Frailty Index, Multimorbidity, Self-rated health, cardiovascular disease, and all-cause mortality. RESULTS: Using between-within models to adjust for shared familial factors, we found that the relationship between educational level and health and mortality later in life persisted despite controlling for familial confounding. PGSEdu and attained education both uniquely predicted late-life health and mortality, even when mutually adjusted. Between-within models of PGSEdu on the health outcomes in dizygotic twins showed weak evidence for passive GE correlation (prGE) in the education-health relationship. DISCUSSION: Both genetic propensity to education and attained education are (partly) independently associated with health in late life. These results lend further support for a causal education-health relationship but also raise the importance of genetic contributions and GE interplay.

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BACKGROUND: Childhood maltreatment (CM) is a strong risk factor for psychiatric disorders but serves in its current definitions as an umbrella for various fundamentally different childhood experiences. As first step toward a more refined analysis of the impact of CM, our objective is to revisit the relation of abuse and neglect, major subtypes of CM, with symptoms across disorders. METHODS: Three longitudinal studies of major depressive disorder (MDD, N = 1240), bipolar disorder (BD, N = 1339), and schizophrenia (SCZ, N = 577), each including controls (N = 881), were analyzed. Multivariate regression models were used to examine the relation between exposure to abuse, neglect, or their combination to the odds for MDD, BD, SCZ, and symptoms across disorders. Bidirectional Mendelian randomization (MR) was used to probe causality, using genetic instruments of abuse and neglect derived from UK Biobank data (N = 143 473). RESULTS: Abuse was the stronger risk factor for SCZ (OR 3.51, 95% CI 2.17-5.67) and neglect for BD (OR 2.69, 95% CI 2.09-3.46). Combined CM was related to increased risk exceeding additive effects of abuse and neglect for MDD (RERI = 1.4) and BD (RERI = 1.1). Across disorders, abuse was associated with hallucinations (OR 2.16, 95% CI 1.55-3.01) and suicide attempts (OR 2.16, 95% CI 1.55-3.01) whereas neglect was associated with agitation (OR 1.24, 95% CI 1.02-1.51) and reduced need for sleep (OR 1.64, 95% CI 1.08-2.48). MR analyses were consistent with a bidirectional causal effect of abuse with SCZ (IVWforward = 0.13, 95% CI 0.01-0.24). CONCLUSIONS: Childhood abuse and neglect are associated with different risks to psychiatric symptoms and disorders. Unraveling the origin of these differences may advance understanding of disease etiology and ultimately facilitate development of improved personalized treatment strategies.

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In Wertz et al. (2019), parents' polygenic scores of educational attainment (PGS-EA) predicted parental sensitive responses to the child's needs for support, as observed in a dyadic task (i.e., observed sensitivity). We aimed to replicate and expand these findings by combining longitudinal data, child genotype data and several polygenic scores in the Generation R Study. Mother-child dyads participated in two developmental periods, toddlerhood (14 months old; n = 648) and early childhood (3-4 years old, n = 613). Higher maternal PGS-EA scores predicted higher observed sensitivity in toddlerhood (b = 0.12, 95% CI 0.03, 0.20) and early childhood (b = 0.16, 95% CI 0.08, 0.24). Child PGS-EA was significantly associated with maternal sensitivity in early childhood (b = 0.11, 95% CI 0.02, 0.21), and the effect of maternal PGS-EA was no longer significant when correcting for child PGS-EA. A latent factor of PGSs based on educational attainment, intelligence (IQ) and income showed similar results. These polygenic scores might be associated with maternal cognitive and behavioral skills that help shape parenting. Maternal PGSs predicted observed sensitivity over and above the maternal phenotypes, showing an additional role for PGSs in parenting research. In conclusion, we replicated the central finding of Wertz et al. (2019) that parental PGS-EA partially explains parental sensitivity. Our findings may be consistent with evocative gene-environment correlation (rGE), emphasizing the dynamic nature of parenting behavior across time, although further research using family trios is needed to adequately test this hypothesis.

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[This corrects the article DOI: 10.3389/fgene.2020.00921.].

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The first part of this review provides a brief historical background of behavior genetic research and how twin and genotype data can be utilized to study genetic influences on individual differences in human behavior. We then review the field of music genetics, from its emergence to large scale twin studies and the recent, first molecular genetic studies of music-related traits. In the second part of the review, we discuss the wider utility of twin and genotype data beyond estimating heritability and gene-finding. We present four examples of music studies that utilized genetically informative samples to analyze causality and gene-environmental interplay for music skills. Overall, research in the field of music genetics has gained much momentum over the last decade and its findings highlight the importance of studying both environmental and genetic factors and particularly their interplay, paving the way for exciting and fruitful times to come.

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The important role of nutrition in proper neural functioning and mental health has seen wider acceptance, but is still sadly under recognized given the existent body of research. This Special Issue was designed to unite authoritative information on this topic in one volume. This editorial provides an overview of the issue, and suggests that the combination of social isolation, lack of exercise, and remaining indoors that overtook industrialized societies during 2020 are specific factors expected to change the Gene × Environment interactions for anxiety and depression. Importantly, the recent environmental changes may make biological diatheses for nutritional deficiencies even more problematic. The concept of G × E interaction is dissected to clarify a non-intuitive scenario: heritability may increase, even when a sharp increase in prevalence is entirely the result of an environmental change (e.g., COVID anxiety and isolation). Key research is highlighted, specific genetic examples are noted, and theoretical implications regarding natural selection are discussed.

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Levine and Sadeh-Sharvit (2023) open the door to a logical and evidence-based targeted prevention strategy adapted from the field of depression. Their proposal is likely to benefit parents who are dealing with their own eating disorders and disordered eating while simultaneously breaking the cycle of risk inherent in the intergenerational transmission of eating disorders. The approach honors the wishes of parents who desperately want to buffer their children from the pain they experienced with their own suffering and provides hope for reducing environmental exposures that could augment any genetic risk that children of affected parents may hold.

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Parenting practices and parental symptoms of attention-deficit/hyperactivity disorder (ADHD) have been linked to severity and course of youth ADHD. However, genetically influenced behaviors related to ADHD in youth may also influence parenting behaviors. Polygenic scores (PGS) have been widely used to quantify genetic vulnerability for ADHD but has rarely been used to examine gene-environment correlation effects. The current study examined the direct effects of youth ADHD PGS and its evocative effects on parenting behaviors via youth ADHD symptoms. 803 youth aged 6-18 years (58.5% male) completed a multistage, multi-informant assessment that included measures of parenting practices and youth and parental ADHD symptoms. A mediation model was used to evaluate direct and evocative effects. Furthermore, we examined if these evocative effects remain after controlling for parental ADHD symptoms. Sensitivity analyses across age, sex, and socioeconomic status (SES) as well as restricting ancestry groups to European only ancestry were also conducted. Results indicated that youth ADHD PGS reliably predicted youth ADHD symptoms across all models (ßs ranging from 0.18 to 0.26), including across age, sex, and SES and held even with ancestry restricted to the largest group (northern European). Evocative effects emerged such that higher youth PGS significantly predicted more youth ADHD symptoms, which in turn, significantly predicted lower levels of parental involvement and higher levels of poor supervision/monitoring and inconsistent discipline. These effects remained after controlling for parent ADHD symptoms.

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Distinguishing between the effects of nature and nurture constitutes a major research goal for those interested in understanding human development. It is known, for example, that many parent traits predict mental health outcomes in children, but the causal processes underlying such associations are often unclear. Family-based quasi-experimental designs such as sibling comparison, adoption and extended family studies have been used for decades to distinguish the genetic transmission of risk from the environmental effects family members potentially have on one another. Recently, these designs have been combined with genomic data, and this combination is fuelling a range of exciting methodological advances. In this review we explore these advances - highlighting the ways in which they have been applied to date and considering what they are likely to teach us in the coming years about the aetiology and intergenerational transmission of psychopathology.

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Although there is evidence for non-shared environmental links between parenting and problem behavior, so far, age-, informant-, and parent-specific patterns for both internalizing and externalizing problem behaviors have not been examined within one study yet. Using the twin differences design, the present study aimed to test how maternal and paternal parenting systematically act as a source of non-shared environment for problem behavior across different age groups and informants. We examined 1327 monozygotic twin pairs and their parents drawn from three birth cohorts of the German TwinLife study. Our results revealed that particularly child-reported less positive and more negative parenting by both parents contribute significantly to the unique environmental variance of problem behavior, although we did not find a clear pattern across age groups. Our study underlines the necessity of controlling for genetic confounding to uncover the truly environmentally mediated (and thus environmentally influenceable) pathways between parenting and problem behavior. A practical implication could be that it may be useful to primarily consider the child's perspective and focus on maternal as well as paternal parenting in interventions that address parenting to reduce problem behavior.

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BACKGROUND: Specific pathways of intergenerational transmission of behavioral traits remain unclear. Here, we aim to investigate how parental genetics influence offspring cognition, educational attainment, and psychopathology in youth. METHODS: Participants for the discovery sample were 2,189 offspring (aged 6-14 years), 1898 mothers and 1,017 fathers who underwent genotyping, psychiatric, and cognitive assessments. We calculated polygenic scores (PGS) for cognition, educational attainment, attention-deficit hyperactivity disorder (ADHD), and schizophrenia for the trios. Phenotypes studied included educational and cognitive measures, ADHD and psychotic symptoms. We used a stepwise approach and multiple mediation models to analyze the effect of parental PGS on offspring traits via offspring PGS and parental phenotype. Significant results were replicated in a sample of 1,029 adolescents, 363 mothers, and 307 fathers. RESULTS: Maternal and paternal PGS for cognition influenced offspring general intelligence and executive function via offspring PGS (genetic pathway) and parental education (phenotypic pathway). Similar results were found for parental PGS for educational attainment and offspring reading and writing skills. These pathways fully explained associations between parental PGS and offspring phenotypes, without residual direct association. Associations with maternal, but not paternal, PGS were replicated. No associations were found between parental PGS for psychopathology and offspring specific symptoms. CONCLUSIONS: Our findings indicate that parental genetics influences offspring cognition and educational attainment by genetic and phenotypic pathways, suggesting the expression of parental phenotypes partially explain the association between parental genetic risk and offspring outcomes. Multiple mediations might represent an effective approach to disentangle distinct pathways for intergenerational transmission of behavioral traits.

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OBJECTIVE: This study examined to what extent genetic and environmental factors explain-either additively or interactively with peer victimization-different trajectories of adolescents' depressive symptoms and whether genetic factors related to distinct trajectories are correlated with peer victimization. METHOD: Participants included 902 twins (52% girls) who self-reported peer victimization and depressive symptoms in grades 6, 7, 8, 9, and 11. RESULTS: Growth mixture modeling revealed 3 trajectories of depressive symptoms: low (69.2% of participants), increasing (19.5%), and high-decreasing-increasing (11.3%). Biometric modeling showed that, for both sexes, genetic factors explained roughly half (52.6%, 47.5%) of the probability of following either a low or an increasing trajectory. Genetic influences (41%) were also observed for the high-decreasing-increasing trajectory, albeit only for girls. Nonshared environmental influences explained the remaining variances, along with shared environmental influences (27%) on the high-decreasing-increasing trajectory. Only for the low and the increasing trajectories, nonshared environmental influences increased with more frequent peer victimization (blow = 0.206, 95% CI [0.094, 0.325]; bincreasing = 0.246, 95% CI [0.143, 0.356]). Moreover, peer victimization was associated with a lower probability of a low trajectory and a higher probability of an increasing or high-decreasing-increasing trajectory, and these associations were mostly explained by common underlying genetic factors. CONCLUSION: Youth expressing (partly inherited) depressive symptoms may be at risk of peer victimization. However, increasing depressive symptoms in victims may be mitigated by other environmental factors except for those who enter adolescence with already high levels of depressive symptoms.

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The purpose of this study was to examine possible pathways by which genetic risk associated with externalizing is transmitted in families. We used molecular data to disentangle the genetic and environmental pathways contributing to adolescent externalizing behavior in a sample of 1,111 adolescents (50% female; 719 European and 392 African ancestry) and their parents from the Collaborative Study on the Genetics of Alcoholism. We found evidence for genetic nurture such that parental externalizing polygenic scores were associated with adolescent externalizing behavior, over and above the effect of adolescents' own externalizing polygenic scores. Mediation analysis indicated that parental externalizing psychopathology partly explained the effect of parental genotype on children's externalizing behavior. We also found evidence for evocative gene-environment correlation, whereby adolescent externalizing polygenic scores were associated with lower parent-child communication, less parent-child closeness, and lower parental knowledge, controlling for parental genotype. These effects were observed among participants of European ancestry but not African ancestry, likely due to the limited predictive power of polygenic scores across ancestral background. These results demonstrate that in addition to genetic transmission, genes influence offspring behavior through the influence of parental genotypes on their children's environmental experiences, and the role of children's genotypes in shaping parent-child relationships.

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Gene-environment correlations and interactions for the relationship between emotional problems (EP) and family environment in adolescents in low- to middle-income countries (LMIC) have been rarely investigated. In total, 3207 adolescent twins aged 12-18 (Mean = 14.6 ± 1.73) years attending public schools in Lagos State in Nigeria completed measures of EP and Family Chaos (FC). Model-fitting analyses suggested that genetic and non-shared environmental influences on EP were 21% and 71%, respectively, and the corresponding estimates were 23% and 71% for FC. Shared environmental influences were not significant (8% and 6% respectively). Phenotypic correlation between EP and FC was .30 (95% CI = .27-.34), which was significantly influenced by genetic (A - 49%, 95% CI: 0.01-0.97) and non-shared environmental factors (E - 32%, 95% CI: 0.10-0.54). Shared environmental influences were not significant (C - 19%, 95% CI: -0.13 to 0.50). Moderation effects were significant whereby as FC increased, A on EP decreased (ßA = -0.07, 95% CI: -0.12 to -0.02) while E increased (ßE = 0.06, 95% CI: 0.03-0.09). Our findings indicate that genetic and non-shared environmental risk factors may mediate the relationship between EP and FC, and that as FC increases, protective genetic influences on EP may be attenuated, whereas environmental influences may become stronger in adolescents in LMIC.

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The synthesis of quantitative genetics and molecular genetics is transforming research in the behavioural sciences. The ability to measure inherited DNA differences directly has led to polygenic scores and to new methods to estimate heritability and genetic correlations. This issue provides examples of how these advances can be appllied to research on gene-environment interplay in developmental psychopathology.

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BACKGROUND: Theoretical models of the development of childhood externalizing disorders emphasize the role of parents. Empirical studies have not been able to identify specific aspects of parental behaviors explaining a considerable proportion of the observed individual differences in externalizing problems. The problem is complicated by the contribution of genetic factors to externalizing problems, as parents provide both genes and environments to their children. We studied the joint contributions of direct genetic effects of children and the indirect genetic effects of parents through the environment on externalizing problems. METHODS: The study used genome-wide single nucleotide polymorphism data from 9,675 parent-offspring trios participating in the Norwegian Mother Father and child cohort study. Based on genomic relatedness matrices, we estimated the contribution of direct genetic effects and indirect maternal and paternal genetic effects on ADHD, conduct and disruptive behaviors at 8 years of age. RESULTS: Models including indirect parental genetic effects were preferred for the ADHD symptoms of inattention and hyperactivity, and conduct problems, but not oppositional defiant behaviors. Direct genetic effects accounted for 11% to 24% of the variance, whereas indirect parental genetic effects accounted for 0% to 16% in ADHD symptoms and conduct problems. The correlation between direct and indirect genetic effects, or gene-environment correlations, decreased the variance with 16% and 13% for conduct and inattention problems, and increased the variance with 6% for hyperactivity problems. CONCLUSIONS: This study provides empirical support to the notion that parents have a significant role in the development of childhood externalizing behaviors. The parental contribution to decrease in variation of inattention and conduct problems by gene-environment correlations would limit the number of children reaching clinical ranges in symptoms. Not accounting for indirect parental genetic effects can lead to both positive and negative bias when identifying genetic variants for childhood externalizing behaviors.

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Research suggests that both genetic and environmental risk factors are involved in the aetiology of schizophrenia (SCZ) and major depressive disorder (MDD). Importantly, environmental and genetic risk factors are often related as evidenced in gene-environment correlation (rGE), which describes the observation that genetic and environmental factors are associated with each other. It is understood that rGE gets stronger over time as individuals select their environments more actively based on their genetic propensities. However, little is known whether rGEs remain stable over time or change across different development periods. Using data from three British longitudinal cohorts, we investigated whether rGE patterns of polygenic risk scores (PRS) for SCZ and MDD changed over time across childhood and adulthood, as well as across both from birth to age 55 and whether results differed between SCZ and MDD. Overall, the majority of rGEs remained stable across the investigated development periods. Furthermore, the few detected rGE changes which did differ between SCZ and MDD, could not be explained by the confounding of clinical cases and are therefore likely the result of actual changes in environmental and cultural risk factors with genetic susceptibility to SCZ and MDD likely playing a less significant role.

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