Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies.

Genome-wide association studies (GWAS) provide biological insights into disease onset and progression and have potential to produce clinically useful biomarkers. A growing body of GWAS focuses on quantitative and transdiagnostic phenotypic targets, such as symptom severity or biological markers, to enhance gene discovery and the translational utility of genetic findings. The current review discusses such phenotypic approaches in GWAS across major psychiatric disorders. We identify themes and recommendations that emerge from the literature to date, including issues of sample size, reliability, convergent validity, sources of phenotypic information, phenotypes based on biological and behavioral markers such as neuroimaging and chronotype, and longitudinal phenotypes. We also discuss insights from multi-trait methods such as genomic structural equation modelling. These provide insight into how hierarchical 'splitting' and 'lumping' approaches can be applied to both diagnostic and dimensional phenotypes to model clinical heterogeneity and comorbidity. Overall, dimensional and transdiagnostic phenotypes have enhanced gene discovery in many psychiatric conditions and promises to yield fruitful GWAS targets in the years to come.

Linking genetic foundations of sleep disturbances to personality traits: a study of mid-life twins.

Risk of sleep disturbances depends on individuals' personality, and a large body of evidence indicates that individuals prone to neuroticism, impulsivity, and (low) extraversion are more likely to experience them. Origins of these associations are unclear, but common genetic background may play an important role. Participants included 405 twin pairs (mean age of 54 years; 59% female) from the National Survey of Midlife Development in the United States (MIDUS) who reported on their personality traits (broad and specific), as well as sleep disturbances (problems with falling asleep, staying asleep, waking early, and feeling unrested). Uni- and bivariate biometric decompositions evaluated contributions of genetic and environmental factors to associations between personality and poor sleep, as well as unique contributions from individual traits. Neuroticism, extraversion, conscientiousness, and aggressiveness were the strongest phenotypic predictors of poor sleep. Genetic sources of covariance were about twice as large as non-shared environmental sources, and only shared genetic background accounted for links between aggressiveness and poor sleep. Neuroticism and extraversion accounted for most of the genetic overlap between personality and sleep disturbances. The findings shed light on developmental antecedents of ties between personality and poor sleep, suggesting a larger role of common genetic background than idiosyncratic life experiences. The results also suggest that emotion-related traits play the most important role for poor sleep, compared to other personality traits, and may partially account for genetic associations with other traits.

Maladaptive personality traits and older adult relationship satisfaction: A co-twin control approach to understanding associations.

OBJECTIVE: Maladaptive personality traits have been implicated in romantic relationship dissatisfaction, but the etiology of those links and the degree to which they extend to other types of relationships are unclear. The purpose of this study was to examine associations between maladaptive personality traits and satisfaction in various relationships using a co-twin control design to identify potential environmental contributions. METHOD: The sample consisted of 1340 older adult twin participants from the Minnesota Twin Registry (Mage = 70.3) that completed the Personality Inventory for DSM-5 Faceted Brief Form and Network of Relationships Inventory (Revised for Older Adults). RESULTS: Several maladaptive personality traits were phenotypically associated with relationship dissatisfaction, with detachment and negative affect having the largest effects. Further, within twin pair differences in detachment and negative affect were associated with greater relationship dissatisfaction, suggesting that observed associations were mediated partly by the unique environment, not solely the result of genetic and familial confounding. Both phenotypic and co-twin associations were strongest overall in the romantic partner relationship. CONCLUSION: These findings support the notion that maladaptive personality traits are implicated in interpersonal dysfunction across multiple domains.

Discrimination and anxiety: Using multiple polygenic scores to control for genetic liability.

An established body of research indicates that discrimination is associated with increased symptoms of anxiety and negative affect. However, the association cannot be interpreted unambiguously as an exposure effect because a common set of genetic factors can simultaneously contribute to increased liability for symptoms of anxiety, negative affect, and the perception of discrimination. The present study elucidates the association between discrimination and anxiety/negative affect by implementing strict genetic controls in a large sample of adults. We used data from the biomarker project of the Study of Midlife Development in the United States (MIDUS), a national probability sample of noninstitutionalized, English-speaking respondents aged 25 to 74 y. Participants who consented to provide genetic data were biologically unrelated and of European ancestry as determined by genotype principal components analysis (n = 1,146). A single structural regression model was fit to the data with three measures of discrimination specified to load onto a latent factor and six measures of anxiety and negative affect specified to load onto a second latent factor. After accounting for potential genetic confounds-polygenic scores for anxiety, depression, and neuroticism and the first five genetic principal components-greater discrimination was associated with greater anxiety/negative affect (ß = 0.53, SE = 0.04, P < 0.001). Findings suggest that measures of perceived discrimination should be considered environmental risk factors for anxiety/negative affect rather than indices of genetic liability for anxiety, depression, or neuroticism. Clinical interventions and prevention measures should focus on ways to mitigate the impact of discrimination to improve mental health at the population level.

Development of a TaqMan assay for the detection of 'Candidatus Phytoplasma brasiliense' and assessment by high resolution melt-curve analysis (HRMA).

'Candidatus Phytoplasma brasiliense' (CPB) is a phytoplasma originally discovered in South America and is known to infect a wide variety of economically important crops. It is most prevalent in Hibiscus spp. where it causes witches broom symptoms and papaya where it causes bunchy top. Recently, CPB was documented for the first time in North America in a new host, globe sedge. In this study two qPCR assays are developed, one utilizing high resolution melt curve analysis (HRMA) based on the secA gene and the other a TaqMan assay based on the dnaK gene. The secA/HRMA and dnaK/TaqMana ssay successfully amplified isolates of CPB. Both assays were screened against available isolates of 16SrI, 16SrII and 16SrIV phytoplasmas. The secA/HRMA assay failed to amplify 16SrI, 16SrIII and 16SrIV phytoplasmas but successfully amplified 16SrII phytoplasmas. The resulting Tm products of CPB and 16SrII phytoplasmas displayed a difference of 0.5°C difference, easily distinguishing them by melt curves. The dnaK/TaqMan assay failed to amplify all non-CPB phytoplasma isolates in the study. The development of these assays provides a valuable tool that will significantly improve monitoring programs in Florida and will aid in developing a better fundamental understanding of the epidemiology of this phytoplasma.

Toward a generalized developmental model of psychopathological liabilities and psychiatric disorders.

BACKGROUND: Most psychiatric disorders are associated with several risk factors, but a few underlying psychopathological dimensions account for the common co-occurrence of disorders. If these underlying psychopathological dimensions mediate associations of the risk factors with psychiatric disorders, it would support a trans-diagnostic orientation to etiological research and treatment development. METHOD: An analysis was performed of the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions III (NESARC-III), a US nationally representative sample of non-institutionalized civilian adults, focusing on respondents who were aged ⩾21 (n = 34 712). Structural equation modeling was used to identify the psychopathological dimensions underlying psychiatric disorders; to examine associations between risk factors, psychopathological dimensions and individual disorders; and to test whether associations of risk factors occurring earlier in life were mediated by risk factors occurring later in life. RESULTS: A bifactor model of 13 axis I disorders provided a good fit (CFI = 0.987, TLI = 0.982, and RMSEA = 0.011) including an overall psychopathology factor as measured by all 13 disorders and 2 specific factors, one for externalizing disorders and one for fear-related disorders. A substantial proportion of the total effects of the risk factors occurring early in life were indirectly mediated through factors occurring later in life. All risk factors showed a significant total effect on the general psychopathology, externalizing and fear-related factors. Only 23 of 325 direct associations of risk factors with psychiatric disorders achieved statistical significance. CONCLUSION: Most risk factors for psychiatric disorders are mediated through broad psychopathological dimensions. The central role of these dimensions supports trans-diagnostic etiological and intervention research.

Comparing associations between personality and loneliness at midlife across three cultural groups.

OBJECTIVE: Loneliness represents a public health threat given its central role in predicting adverse mental and physical health outcomes. Prior research has established four of the Big Five personality traits as consistent cross-sectional predictors of loneliness in largely western, White samples. However, it is not clear if the personality predictors of loneliness vary across cultures. METHOD: The present study estimates associations between the Big Five traits and loneliness across distinct samples of White American, Black American, and Japanese adults (n = 6051 at T1). Confirmatory factor analysis and exploratory structural equation modeling were used to examine measurement invariance properties of the Big Five and loneliness across these groups. The factor structures were then carried forward to estimate associations between personality and loneliness across two assessments waves using structural equation modeling. RESULTS: While Neuroticism was a strong predictor across groups, low Extraversion was more predictive of loneliness in Japan than in the U.S., and low Conscientiousness was only a significant predictor in the U.S. CONCLUSIONS: Previous literature offers a framework for interpreting these findings in that loneliness may be shaped comparatively more through interconnectedness in Japanese culture, while, in the U.S., individual goals and personal romantic expectations are more salient.

The weight of childhood adversity: evidence that childhood adversity moderates the impact of genetic risk on waist circumference in adulthood.

OBJECTIVE: The present study tested the interactive effects of childhood adversity and polygenic risk scores for waist circumference (PRS-WC) on waist circumference (WC). Consistent with a diathesis-stress model, we hypothesize that the relationship between PRS-WC and WC will be magnified by increasing levels of childhood adversity. METHODS: Observational study of 7976 adults (6347 European Americans and 1629 African Americans) in the Health and Retirement Study with genotyped data. PRS-WC were calculated by the HRS administrative core using the weighted sum of risk alleles based on a genome-wide association study conducted by the Genetic Investigation of Anthropometric Traits (GIANT) consortium. Childhood adversity was operationalized using a sum score of three traumatic events that occurred before the age of 18 years. RESULTS: There was a statistically significant interaction between PRS-WC and childhood adversity for European Americans, whereby the magnitude of PRS-WC predicting WC increased as the number of adverse events increased. CONCLUSIONS: This study supports the idea of the interactive effects of genetic risks and childhood adversity on obesity. More epidemiological studies, particularly with understudied populations, are needed to better understand the roles that genetics and childhood adversity play on the development and progression of obesity.

Changing genetic architecture of body mass index from infancy to early adulthood: an individual based pooled analysis of 25 twin cohorts.

BACKGROUND: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. METHODS: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. RESULTS: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. CONCLUSIONS: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.

The Hierarchical Taxonomy of Psychopathology (HiTOP) in psychiatric practice and research.

The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description.

Assessing the role of socioeconomic status and discrimination exposure for racial disparities in inflammation.

Socioeconomic status (SES) and discrimination have been implicated as social determinants of health and health disparities. Yet, very little research has been done to assess their contributing role in Black-White disparities in inflammation. Using data from the Midlife in the United States (2004-2006), we conducted Oaxaca-Blinder decomposition analysis to quantify the extent to which three indicators of SES (i.e., education, household income, and employment status) and three forms of discrimination exposures (i.e., everyday, lifetime, and workplace discrimination) explained Black-White differences in inflammation. Education, particularly having a college degree or more, explained 16.88% of the differences between Blacks and Whites. There was no evidence that household income and employment status explained Black-White inflammation differences. Lifetime discrimination significantly explained 18.18% of Black-White difference in inflammation burden. There was no evidence that everyday and workplace discrimination explained Black-White difference in inflammation burden. Together, the predictors explained 44.16% of inflammation differences between Black and White participants. Education and lifetime exposure to discrimination may play a role in inflammation disparities. Further research is needed to examine other dimensions of SES (e.g., wealth) and discrimination (e.g., racial segregation) that are associated with health to better understand the contributions of these key social determinants of Black-White inflammation disparities.

Psychiatric disorders and risk for multiple adverse outcomes: a national prospective study.

Most psychiatric disorders, when examined individually, are associated with a broad range of adverse outcomes. However, psychiatric disorders often co-occur and their co-occurrence is well explained by a limited number of transdiagnostic factors. Yet it remains unclear whether the risk of these adverse outcomes is due to specific psychiatric disorders, specific dimensions of psychopathology (i.e., internalizing and externalizing dimensions), a general psychopathology factor, or a combination of these explanations. In a large nationally representative prospective survey, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we used structural equation modeling to examine the shared and specific effects of common Axis I and Axis II disorders on the risk of ten adverse outcomes (unemployment; financial crisis; low income; poorer general health; worse mental and physical health; legal problems; divorce; problems with a neighbor, friend, or relative; and violence) in the general adult population. Effects of psychiatric disorders were exerted mostly through a general psychopathology factor representing the shared effect across all disorders, independent of sociodemographic characteristics and the presence of the adverse outcomes at baseline. Violence and legal problems were further associated with the externalizing factor, but there were no independent associations of the internalizing factor or any individual psychiatric disorders with any of the adverse outcomes. Our findings reveal that associations between psychiatric disorders and adverse outcomes occur through broad psychological dimensions. Understanding the biological and psychological mechanisms underlying these dimensions should yield key intervention targets to decrease the individual suffering and societal burden associated with common psychiatric disorders.

The relationship between brain structure and general psychopathology in preadolescents.

BACKGROUND: An emerging body of literature has indicated that broad, transdiagnostic dimensions of psychopathology are associated with alterations in brain structure across the life span. The current study aimed to investigate the relationship between brain structure and broad dimensions of psychopathology in the critical preadolescent period when psychopathology is emerging. METHODS: This study included baseline data from the Adolescent Brain and Cognitive Development (ABCD) Study® (n = 11,875; age range = 9-10 years; male = 52.2%). General psychopathology, externalizing, internalizing, and thought disorder dimensions were based on a higher-order model of psychopathology and estimated using Bayesian plausible values. Outcome variables included global and regional cortical volume, thickness, and surface area. RESULTS: Higher levels of psychopathology across all dimensions were associated with lower volume and surface area globally, as well as widespread and pervasive alterations across the majority of cortical and subcortical regions studied, after adjusting for sex, race/ethnicity, parental education, income, and maternal psychopathology. The relationships between general psychopathology and brain structure were attenuated when adjusting for cognitive functioning. There were no statistically significant relationships between psychopathology and cortical thickness in this sample of preadolescents. CONCLUSIONS: The current study identified lower cortical volume and surface area as transdiagnostic biomarkers for general psychopathology in preadolescence. Future research may focus on whether the widespread and pervasive relationships between general psychopathology and brain structure reflect cognitive dysfunction that is a feature across a range of mental illnesses.

Training the Next Generation of Clinical Psychological Scientists: A Data-Driven Call to Action.

The central goal of clinical psychology is to reduce the suffering caused by mental health conditions. Anxiety, mood, psychosis, substance use, personality, and other mental disorders impose an immense burden on global public health and the economy. Tackling this burden will require the development and dissemination of intervention strategies that are more effective, sustainable, and equitable. Clinical psychology is uniquely poised to serve as a transdisciplinary hub for this work. But rising to this challengerequires an honest reckoning with the strengths and weaknesses of current training practices. Building on new data, we identify the most important challenges to training the next generation of clinical scientists. We provide specific recommendations for the full spectrum of stakeholders-from funders, accreditors, and universities to program directors, faculty, and students-with an emphasis on sustainable solutions that promote scientific rigor and discovery and enhance the mental health of clinical scientists and the public alike.

The distinction between symptoms and traits in the Hierarchical Taxonomy of Psychopathology (HiTOP).

The Hierarchical Taxonomy of Psychopathology (HiTOP) is an empirically and quantitatively derived dimensional classification system designed to describe the features of psychopathology and, ultimately, to replace categorical nosologies. Among the constructs that HiTOP organizes are "symptom components" and "maladaptive traits," but past HiTOP publications have not fully explicated the distinction between symptoms and traits. We propose working definitions of symptoms and traits and explore challenges, exceptions, and remaining questions. Specifically, we propose that the only systematic difference between symptoms and traits in HiTOP is one of time frame. Maladaptive traits are dispositional constructs that describe persistent tendencies to manifest features of psychopathology, whereas symptoms are features of psychopathology as they are manifest during any specific time period (from moments to days to months). This has the consequence that almost every HiTOP dimension, at any level of the hierarchy, can be assessed as either a trait or a symptom dimension, by adjusting the framing of the assessment. We discuss the implications of these definitions for causal models of the relations between symptoms and traits and for distinctions between psychopathology, normal personality variation, and dysfunction.

Cultural evolution and behavior genetic modeling: The long view of time.

We advocate for an integrative long-term perspective on time, noting that culture changes on timescales amenable to behavioral genetic study with appropriate design and modeling extensions. We note the need for replications of behavioral genetic studies to examine model invariance across long-term timescales, which would afford examination of specified as well as unspecified cultural moderators of behavioral genetic effects.

Variability in the stability of personality traits across a single combat deployment.

This study assessed changes in measures of personality traits across a 12-month combat deployment in a sample of conventional US Army soldiers. Results revealed Impulsive Sensation-Seeking (ImpSS) and Sociability (Sy) decreased significantly, whereas Neuroticism-Anxiety (N-Anx) increased. Changes in ImpSS scores were mainly attributed to age, but were inversely related to increases in traumatic stress symptoms. Combat exposure, concussion, age, education, and changes in traumatic stress scores all independently contributed to changes in N-Anx scores. Changes in Sy were not associated with any of the data available from pre-deployment or deployment measures. Changes in Aggression-hostility (Agg-Hos) and Activity (Act) across the deployment were not significant. The findings suggest significant variability in the stability of personality traits when exposed to combat stress and injury while deployed, which may be influenced by factors such as age and education.

Task-related neural mechanisms of persecutory ideation in schizophrenia and community monozygotic twin-pairs.

Perceptions of spiteful behavior are common, distinct from rational fear, and may undergird persecutory ideation. To test this hypothesis and investigate neural mechanisms of persecutory ideation, we employed a novel economic social decision-making task, the Minnesota Trust Game (MTG), during neuroimaging in patients with schizophrenia (n = 30) and community monozygotic (MZ) twins (n = 38; 19 pairs). We examined distinct forms of mistrust, task-related brain activation and connectivity, and investigated relationships with persecutory ideation. We tested whether co-twin discordance on these measurements was correlated to reflect a common source of underlying variance. Across samples persecutory ideation was associated with reduced trust only during the suspiciousness condition, which assessed spite sensitivity given partners had no monetary incentive to betray. Task-based activation contrasts for specific forms of mistrust were limited and unrelated to persecutory ideation. However, task-based connectivity contrasts revealed a dorsal cingulate anterior insula network sensitive to suspicious mistrust, a left frontal-parietal (lF-P) network sensitive to rational mistrust, and a ventral medial/orbital prefrontal (vmPFC/OFC) network that was sensitive to the difference between these forms of mistrust (all p < .005). Higher persecutory ideation was predicted only by reduced connectivity between the vmPFC/OFC and lF-P networks (p = .005), which was only observed when the intentions of the other player were relevant. Moreover, co-twin differences in persecutory ideation predicted co-twin differences in both spite sensitivity and in vmPFC/OFC-lF-P connectivity. This work found that interconnectivity may be particularly important to the complex neurobiology underlying persecutory ideation, and that unique environmental variance causally linked persecutory ideation, decision-making, and brain connectivity.

Educational attainment of same-sex and opposite-sex dizygotic twins: An individual-level pooled study of 19 twin cohorts.

Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (ß = -0.05 educational years, 95% CI -0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (ß = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers.

The Hierarchical Taxonomy of Psychopathology (HiTOP): A Quantitative Nosology Based on Consensus of Evidence.

Traditional diagnostic systems went beyond empirical evidence on the structure of mental health. Consequently, these diagnoses do not depict psychopathology accurately, and their validity in research and utility in clinicalpractice are therefore limited. The Hierarchical Taxonomy of Psychopathology (HiTOP) consortium proposed a model based on structural evidence. It addresses problems of diagnostic heterogeneity, comorbidity, and unreliability. We review the HiTOP model, supporting evidence, and conceptualization of psychopathology in this hierarchical dimensional framework. The system is not yet comprehensive, and we describe the processes for improving and expanding it. We summarize data on the ability of HiTOP to predict and explain etiology (genetic, environmental, and neurobiological), risk factors, outcomes, and treatment response. We describe progress in the development of HiTOP-based measures and in clinical implementation of the system. Finally, we review outstanding challenges and the research agenda. HiTOP is of practical utility already, and its ongoing development will produce a transformative map of psychopathology.