Without even knowing of their existence, Mendel discovered how genes operate when they are completely penetrant, although they rarely are, at least with respect to human personality and psychopathology; yet quantitative genetics results have conclusively demonstrated their substantial macrolevel influence. Now we need to understand just how incompletely penetrant genes make their contributions to psychopathology. Exciting new developments in molecular genetics and epigenetics provide new insight into gene action in principle but have been of limited value so far in understanding the emergence of psychopathology. Some of the most helpful postulates might come from evolutionary and developmental biology and agricultural breeding experiments. I describe the all but forgotten evolutionary mechanisms articulated by Schmalhausen, a Russian evolutionary biologist whose work was suppressed by Stalin in the 1940s. I focus on Schmalhausen's law, the observation that organisms living in conditions at the boundary of their tolerance in any one aspect of existence will be vulnerable to expression of genetic liabilities related to all other aspects of existence. I show how Schmalhausen's ideas are relevant to the results of a century-long corn-breeding experiment and the current concepts of facilitated variation and cryptic genetic variation. I then discuss the relevance of all of these to understanding genetic influences on personality and psychopathology.

Despite substantial recent advancements in psychiatric genetic research, progress in identifying the genetic basis of anxiety disorders has been limited. We review the candidate gene and genome-wide literatures in anxiety, which have made limited progress to date. We discuss several reasons for this hindered progress, including small samples sizes, heterogeneity, complicated comorbidity profiles, and blurred lines between normative and pathological anxiety. To address many of these challenges, we suggest a developmental, multivariate framework that can inform and enhance anxiety phenotypes for genetic research. We review the psychiatric and genetic epidemiological evidence that supports such a framework, including the early onset and chronic course of anxiety disorders, shared genetic risk factors among disorders both within and across time, and developmentally dynamic genetic influences. We propose three strategies for developmentally sensitive phenotyping: examination of early temperamental risk factors, use of latent factors to model underlying anxiety liability, and use of developmental trajectories as phenotypes. Expanding the range of phenotypic approaches will be important for advancing studies of the genetic architecture of anxiety disorders.

This article serves to outline a research paradigm to investigate main effects and interactions of genes, environment, and development on behavior and psychiatric illness. We provide a historical context for candidate gene studies and genome-wide association studies, including benefits, limitations, and expected payoffs. Using substance use and abuse as our driving example, we then turn to the importance of etiological psychological theory in guiding genetic, environmental, and developmental research, as well as the utility of refined phenotypic measures, such as endophenotypes, in the pursuit of etiological understanding and focused tests of genetic and environmental associations. Phenotypic measurement has received considerable attention in the history of psychology and is informed by psychometrics, whereas the environment remains relatively poorly measured and is often confounded with genetic effects (i.e., gene–environment correlation). Genetically informed designs, which are no longer limited to twin and adoption studies thanks to ever-cheaper genotyping, are required to understand environmental influences. Finally, we outline the vast amount of individual difference in structural genomic variation, most of which remains to be leveraged in genetic association tests. Although the genetic data can be massive and burdensome (tens of millions of variants per person), we argue that improved understanding of genomic structure and function will provide investigators with new tools to test specific a priori hypotheses derived from etiological psychological theory, much like current candidate gene research but with less confusion and more payoff than candidate gene research has to date.

Adverse early care is associated with attention regulatory problems, but not all so exposed develop attention problems. In a sample of 612 youth (girls = 432, M = 11.82 years, SD = 1.5) adopted from institutions (e.g., orphanages) in 25 countries, we examined whether the Val66Met polymorphism of the brain-derived neurotrophic factor gene moderates attention problems associated with the duration of institutional care. Parent-reported attention problem symptoms were collected using the MacArthur Health and Behavior Questionnaire. DNA was genotyped for the brain-derived neurotrophic factor Val66Met (rs6265) single nucleotide polymorphism. Among youth from Southeast (SE) Asia, the predominant genotype was valine/methionine (Val/Met), whereas among youth from Russia/Europe and Caribbean/South America, the predominant genotype was Val/Val. For analysis, youth were grouped as carrying Val/Val or Met/Met alleles. Being female, being from SE Asia, and being younger when adopted were associated with fewer attention regulatory problem symptoms. Youth carrying at least one copy of the Met allele were more sensitive to the duration of deprivation, yielding an interaction that followed a differential susceptibility pattern. Thus, youth with Val/Met or Met/Met genotypes exhibited fewer symptoms than Val/Val genotypes when adoption was very early and more symptoms when adoption occurred later in development. Similar patterns were observed when SE Asian youth and youth from other parts of the world were analyzed separately.

A functional promoter polymorphism of the nitric oxide synthase 1 gene first exon 1f variable number tandem repeat (NOS1 ex1f-VNTR) is associated with impulsivity and related psychopathology. Facets of impulsivity are strongly associated with personality traits; maladaptive impulsivity with neuroticism; and adaptive impulsivity with extraversion. Both high neuroticism and low extraversion predict anxiety and depressive symptoms. The aim of the present study was to evaluate the effect of the NOS1 ex1f-VNTR genotype and possible interaction with environmental factors on personality, anxiety, and depressiveness in a population-representative sample. Short allele carriers had higher neuroticism and anxiety than individuals with the long/long (l/l) genotype. Male short/short homozygotes also had higher extraversion. In the face of environmental adversity, females with a short allele had higher scores of neuroticism, anxiety, and depressiveness compared to the l/l genotype. Males were more sensitive to environmental conditions when they had the l/l genotype and low extraversion. In conclusion, the NOS1 ex1f-VNTR influences personality and emotional regulation dependent on gender and environment. Together with previous findings on the effect of the NOS1 genotype on impulse control, these data suggest that NOS1 should be considered another plasticity gene, because its variants are associated with different coping strategies.

Childhood maltreatment is associated with lasting changes in neuroendocrine regulation, alterations in brain structure and function, and symptoms of “limbic irritability.” Limbic irritability symptoms include somatic, sensory, and behavioral phenomena and may stem from increased excitatory neurotransmission following maltreatment. We tested the hypotheses that child maltreatment is indirectly associated with depressive and dissociative symptomatology via indicators of limbic irritability and that variation within the FK506 binding protein 5 gene (FKBP5), a gene involved in glucorticoid receptor functioning, moderates these effects. The sample consisted of high-risk, low-income women (N = 236) living in an inner-city environment. Child maltreatment, limbic irritability, and symptoms of depression and dissociation were measured cross-sectionally using self-report assessments. Haplotype analyses were conducted across four FKBP5 single nucleotide polymorphisms: rs3800373, rs9296158, rs1360870, and rs9470080. Path analysis using bootstrapping procedures was performed to test hypotheses regarding indirect and conditional indirect effects. We found significant indirect effects of maltreatment on depression (β = 0.088, p < .01) and dissociation (β = 0.105, p < .01) via limbic irritability. In addition, variation within FKBP5 moderated these significant indirect effects. For individuals with one to two copies of the CATT haplotype, the indirect effects of maltreatment on depression (β = 0.137, p < .01) and dissociation (β = 0.132, p < .01) via limbic irritability were significant, whereas the indirect paths were not significant for individuals with no copies of this haplotype (depression: β = 0.037, p > .05; dissociation: β = 0.002, p > .05). These results add to the growing evidence that child maltreatment may lead to symptoms of internalizing psychopathology through its impact on the limbic system. In addition, this study revealed a potential role of FKBP5 gene variants in contributing to risk for limbic system dysfunction.

The significance of genotype–environment interplay is its focus on how causal factors, whether environmental or genetic, have their effects. It is difficult to establish causality in observational research because of the potential for reverse causation and confounding. Most environmental measures are heritable, which means that their effects on the risk for psychopathology are potentially confounded by genotype. In contrast, genetic influences on psychopathology may be mediated by their effect on environmental exposures. The existence of genetic influences on putative environmental risk factors offers both possibilities and pitfalls for research into environmental epidemiology. We use the example of parenting and its influence on childhood externalizing problems to review how genotype–environment correlations can be exploited to demonstrate causal processes in pyschopathology.

Academic performance during the first years of school lays the groundwork for subsequent trajectories of academic success throughout childhood and adolescence. The current study tests a model according to which a gene–parenting correlation in the first 3 years of life is associated with subsequent psychosocial adjustment and then academic performance in the first grade (as indicated by teachers' assessment of academic behavior and two subscales of the Woodcock–Johnson Test of Achievement, Third Edition). Drawing on multiple waves of data from the Durham Child Health and Development Study, we find that risk alleles for dopamine receptor genes (dopamine receptor D4 for girls, dopamine receptor D2 for boys) are associated with less sensitive parenting. For girls, parenting mediates the link between dopamine receptor D4 and all academic outcomes. There is some indication that parenting also influences girls' withdrawn behavior in the classroom, which in turn influences teachers' assessments of academic performance. For boys, some evidence suggests that parenting is associated with emotion regulation, which is associated with teachers' assessments of academic behavior and both subscales of the Woodcock–Johnson. Replications of this exploratory study are necessary, but these findings provide a first step in understanding how evocative correlations in the home may predict indicators of psychosocial adjustment that in turn influence performance and achievement at school.

Past research has linked interparental conflict, parent psychopathology, hostile parenting, and externalizing behavior problems in childhood. However, few studies have examined these relationships while simultaneously allowing the contribution of common genetic factors underlying associations between family- and parent-level variables on child psychopathology to be controlled. Using the attributes of a genetically sensitive in vitro fertilization research design, the present study examined associations among interparental conflict, parents' antisocial behavior problems, parents' anxiety symptoms, and hostile parenting on children's antisocial behavior problems among genetically related and genetically unrelated mother–child and father–child groupings. Path analyses revealed that for genetically related mothers, interparental conflict and maternal antisocial behavior indirectly influenced child antisocial behavior through mother-to-child hostility. For genetically unrelated mothers, effects were apparent only for maternal antisocial behavior on child antisocial behavior through mother-to-child hostility. For both genetically related and genetically unrelated fathers and children, interparental conflict and paternal antisocial behavior influenced child antisocial behavior through father-to-child hostility. Effects of parental anxiety symptoms on child antisocial behavior were apparent only for genetically related mothers and children. Results are discussed with respect to the relative role of passive genotype–environment correlation as a possible confounding factor underlying family process influences on childhood psychopathology.

The past decade has witnessed an exponential growth in studies that have attempted to identify the genetic polymporphisms that moderate the influence of environmental risks on mental disorders. What tends to be neglected in these Gene × Environment (G × E) interaction studies has been a focus on resilience, which refers to a dynamic pattern of positive adaptation despite the experience of a significant trauma or adversity. In this article, we argue that one step toward advancing the field of developmental psychopathology would be for G × E research to consider resilience instead of focusing almost exclusively on mental disorders. After providing an up-to-date summary on the expanding definitions and models of resilience, and the available evidence regarding measured G × E studies of childhood maltreatment, we discuss why resilience would be a worthwhile phenotype for studies of measured G × E. First, although G × E hypotheses require that there be an environmental risk (e-risk) involved in a causal process that leads to psychopathology, e-risks are typically not included in the diagnostic criteria for most psychiatric disorders. In contrast, resilience by definition includes an e-risk. Second, G × E hypotheses require that there is evidence of variability in response to an environmental stressor, and resilience often represents the positive end on this continuum of adaptation. Third, both resilience and G × E are best understood from a developmental perspective. Fourth, although resilient outcomes are not public health concerns, the types of adversities (e.g., childhood maltreatment, poverty, or exposure to natural disasters) that are often investigated in studies of resilience certainly are. Understanding how some individuals, perhaps because of their genetic makeup, are able to withstand such adversities can inform prevention and intervention efforts to improve mental health.

Despite the substantial heritability of nearly all psychological traits, it has been difficult to identify specific genetic variants that account for more than a tiny percentage of genetic variance in phenotypes. Common explanations for this “missing heritability” include massive polygenicity, rare variants, epigenetics, epistasis, and gene–environment interactions. Gene–trait (G × T) interaction is another concept useful for understanding the lack of obvious genetic main effects. Both genes and environments are distal contributors to human behavior, but the brain is the proximal driver of behavior. The effect of any single genetic variant is dependent on the configuration of the brain in which it is expressed. One method to begin studying how single genes interact with variations in the rest of the brain is to investigate G × T interactions. A psychological trait reflects a characteristic pattern of psychological function (and, therefore, of brain function), which has its origin in the cumulative effects of both the genome and the environment. A trait therefore describes variation in the broad organismic context in which any single gene operates. We describe the nature and significance of G × T interactions for understanding psychopathology and normal trait variation, which are illustrated with empirical examples.

A wide range of developmental disorders present with characteristic psychopathologies and behaviors, with diagnoses including, inter alia, cognitive disorders and learning disabilities, epilepsies, autism, and schizophrenia. Each, to varying extent, has a genetic component to etiology and is associated with cytogenetic abnormalities. Technological developments, particularly array-based comparative genome hybridization and single nucleotide polymorphism chips, has revealed a wide range of rare recurrent and de novo copy number variants (CNVs) to be associated with disorder and psychopathology. It is surprising that many apparently similar CNVs are identified across two or more disorders hitherto considered unrelated. This article describes the characteristics of CNVs and current technological restrictions that make accurately identifying small events difficult. It summarizes the latest discoveries for individual diagnostic categories and considers the implications for a shared neurobiology. It examines likely developments in the knowledge base as well as addressing the clinical implications going forward.

Copy number variants (CNVs) are submicroscopic deletions and duplications of genomic material that were previously thought to be rare phenomena. They have now been robustly associated with a variety of disorders such as autism, schizophrenia, and attention-deficit/hyperactivity disorder through an emerging research base in affective disorders. A complex picture is emerging of a polygenic, heterogeneous model of disease, with CNVs conferring broad susceptibility to a variety of neurodevelopmental disorders, rather than specific disorders per se. Although the insights gleaned thus far only represent a small piece of a much larger puzzle, progress has been rapid and new technologies promise even more insights into these hitherto opaque brain disorders. We will discuss CNVs, the current state of evidence for their role in the pathogenesis of classical psychiatric disorders, and the application of such knowledge in clinical settings.

Based on numerous suggestions in the literature, we evaluated lexical decision (LD) as a putative endophenotype for reading comprehension by investigating heritability estimates and segregation analyses parameter estimates for both of these phenotypes. Specifically, in a segregation analysis of a large sample of families, we established that there is little to no overlap between genes contributing to LD and reading comprehension and that the genetic mechanism behind LD derived from this analysis appears to be more complex than that for reading comprehension. We conclude that in our sample, LD is not a good candidate as an endophenotype for reading comprehension, despite previous suggestions from the literature. Based on this conclusion, we discuss the role and benefit of the endophenotype approach in studies of complex human cognitive functions.

Prenatal exposure to maternal stress, anxiety, and depression can have lasting effects on infant development with risk of psychopathology. Although the impact of prenatal maternal distress has been well documented, the potential mechanisms through which maternal psychosocial variables shape development have yet to be fully elucidated. Advances in molecular biology have highlighted the role of epigenetic mechanisms in regulating gene activity, neurobiology, and behavior and the potential role of environmentally induced epigenetic variation in linking early life exposures to long-term biobehavioral outcomes. In this article, we discuss evidence illustrating the association between maternal prenatal distress and both fetal and infant developmental trajectories and the potential role of epigenetic mechanisms in mediating these effects. Postnatal experiences may have a critical moderating influence on prenatal effects, and we review findings illustrating prenatal–postnatal interplay and the developmental and epigenetic consequences of postnatal mother–infant interactions. The in utero environment is regulated by placental function and there is emerging evidence that the placenta is highly susceptible to maternal distress and a target of epigenetic dysregulation. Integrating studies of prenatal exposures, placental function, and postnatal maternal care with the exploration of epigenetic mechanisms may provide novel insights into the pathophysiology induced by maternal distress.

The period of in utero development is one of the most critical windows during which adverse intrauterine conditions and exposures can influence the growth and development of the fetus as well as the child's future postnatal health and behavior. Maternal cigarette smoking during pregnancy remains a relatively common but nonetheless hazardous in utero exposure. Previous studies have associated prenatal smoke exposure with reduced birth weight, poor developmental and psychological outcomes, and increased risk for diseases and behavioral disorders later in life. Researchers are now learning that many of the mechanisms whereby maternal smoke exposure may affect key pathways crucial for proper fetal growth and development are epigenetic in nature. Maternal cigarette smoking during pregnancy has been associated with altered DNA methylation and dysregulated expression of microRNA, but a deeper understanding of the epigenetics of maternal cigarette smoking during pregnancy as well as how these epigenetic changes may affect later health and behavior remain to be elucidated. This article seeks to explore many of the previously described epigenetic alterations associated with maternal cigarette smoking during pregnancy and assess how such changes may have consequences for both fetal growth and development, as well as later child health, behavior, and well-being. We also outline future directions for this new and exciting field of research.

In humans, it has been demonstrated that the serotonin transporter linked polymorphic region (5-HTTLPR) genotype moderates risk in the face of adversity. One mechanism by which stress could interact with genotype is via epigenetic modifications. We wanted to examine whether stress interacted with genotype to predict binding of a histone 3 protein trimethylated at lysine 3 (H3K4me3) that marks active promoters. The brains (N = 61) of male rhesus macaques that had been reared in the presence or absence of stress were archived and the hippocampusi dissected. Chromatin immunoprecipitation was performed with an antibody against H3K4me3 followed by sequencing on a SolexaG2A. The effects of age, genotype (5-HTTLPR long/long vs. short), and stress exposure (peer-reared vs. mother-reared) on levels of H3K4me3 binding were determined. We found effects of age and stress exposure. There was a decline in H3K4me3 from preadolescence to postadolescence and lower levels in peer-reared monkeys and no effects of genotype. When we controlled for age, however, we found that there were effects of 5-HTTLPR genotype and rearing condition on H3K4me3 binding. In a larger sample, we observed that cerebrospinal fluid 5-hydroxyindoleacetic acid levels were subject to interactive effects among age, rearing history, and genotype. Genes containing both genetic selection and epigenetic regulation may be particularly important in stress adaptation and development. We find evidence for selection at the solute carrier family C6 member 4 gene and observe epigenetic reorganization according to genotype, stress, and age. These data suggest that developmental stage may moderate effects of stress and serotonin transporter genotype in the emergence of alternative adaptation strategies and in the vulnerability to developmental or psychiatric disorders.

Child neglect is the most prevalent form of child maltreatment in the United States, and poses a serious public health concern. Children who survive such episodes go on to experience long-lasting psychological and behavioral problems, including higher rates of post-traumatic stress disorder symptoms, depression, alcohol and drug abuse, attention-deficit/hyperactivity disorder, and cognitive deficits. To date, most research into the causes of these life-long problems has focused on well-established targets such as stress responsive systems, including the hypothalamus–pituitary–adrenal axis. Using the maternal separation and early weaning model, we have attempted to provide comprehensive molecular profiling of a model of early-life neglect in an organism amenable to genomic manipulation: the mouse. In this article, we report new findings generated with this model using chromatin immunoprecipitation sequencing, diffuse tensor magnetic resonance imaging, and behavioral analyses. We also review the validity of the maternal separation and early weaning model, which reflects behavioral deficits observed in neglected humans including hyperactivity, anxiety, and attentional deficits. Finally, we summarize the molecular characterization of these animals, including RNA profiling and label-free proteomics, which highlight protein translation and myelination as novel pathways of interest.

In recent years, translational research involving humans and animals has uncovered biological and physiological pathways that explain associations between early adverse circumstances and long-term mental and physical health outcomes. In this article, we summarize the human and animal literature demonstrating that epigenetic alterations in key biological systems, the hypothalamus–pituitary–adrenal axis and immune system, may underlie such disparities. We review evidence suggesting that changes in DNA methylation profiles of the genome may be responsible for the alterations in hypothalamus–pituitary–adrenal axis and immune system trajectories. Using some preliminary data, we demonstrate how explorations of genome-wide and candidate-gene DNA methylation profiles may inform hypotheses and guide future research efforts in these areas. We conclude our article by discussing the many important future directions, merging perspectives from developmental psychology, molecular genetics, neuroendocrinology, and immunology, that are essential for furthering our understanding of how early adverse circumstances may shape developmental trajectories, particularly in the areas of stress reactivity and physical or mental health.