Irwin Waldman

• Emory University

Psychiatric disorders exhibit substantial genetic overlap, raising questions about the utility of transdiagnostic genetic risk models. Using data from the All of Us Research Program (N=102,091), we evaluated common psychiatric genetic (CPG) factor-based polygenic risk scores (PRSs) compared to standard disorder-specific PRSs. The CPG PRS consistent...

Bipolar disorder is a leading contributor to the global burden of disease¹. Despite high heritability (60–80%), the majority of the underlying genetic determinants remain unknown². We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combi...

Psychiatric disorders display high levels of comorbidity and genetic overlap. Genomic methods have shown that even for schizophrenia and bipolar disorder, two disorders long-thought to be etiologically distinct, the majority of genetic signal is shared. Furthermore, recent cross-disorder analyses have uncovered over a hundred pleiotropic loci share...

Consistent evidence has documented the cross-sectional and longitudinal associations of externalizing psychopathology with personality and behavioral traits, suggesting the presence of a broad, underlying liability to externalizing. In one of the first studies of its kind, we use a large, representative sample of youth (N = 2,245 twins and their si...

Importance: Substance use disorders (SUDs) frequently co-occur with each other and with other traits related to behavioral disinhibition, a spectrum of outcomes referred to as externalizing. Nevertheless, genome-wide association studies (GWAS) typically study individual SUDs separately. This single-disorder approach ignores genetic covariance betwe...

Features of autism spectrum disorder, attention‐deficit/hyperactivity disorder, learning disorders, intellectual disabilities, and communication and motor disorders usually emerge early in life and are associated with atypical neurodevelopment. These “neurodevelopmental conditions” are grouped together in the DSM‐5 and ICD‐11 to reflect their share...

Failures of self-control can manifest as externalizing behaviors (e.g., aggression, rule-breaking) that have far-reaching negative consequences. Researchers have long been interested in measuring children’s genetic risk for externalizing behaviors to inform efforts at early identification and intervention. Drawing on data from the Environmental Ris...

Externalizing psychopathology has been found to have small to moderate associations with neighborhood and family sociodemographic characteristics. However, prior studies may have used suboptimal operationalizations of neighborhood sociodemographic characteristics and externalizing psychopathology, potentially misestimating relations between these c...

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD...

Quantitative, empirical approaches to establishing the structure of psychopathology hold promise to improve on traditional psychiatric classification systems. The Hierarchical Taxonomy of Psychopathology (HiTOP) is a framework that summarizes the substantial and growing body of quantitative evidence on the structure of psychopathology. To achieve i...

Interest has increased in the recent literature on characterizing psychopathology dimensionally in hierarchical models. One dimension of psychopathology that has received considerable attention is externalizing. Although extensively studied and well-characterized in late adolescents and adults, delineation of the externalizing spectrum in youth has...

Proprietary genetic datasets are valuable for boosting the statistical power of genome-wide association studies (GWASs), but their use can restrict investigators from publicly sharing the resulting summary statistics. Although researchers can resort to sharing down-sampled versions that exclude restricted data, down-sampling reduces power and might...

Substance use disorders (SUDs) are phenotypically and genetically correlated with each other and with other psychological traits characterized by behavioural under‐control, termed externalizing phenotypes. In this study, we used genomic structural equation modelling to explore the shared genetic architecture among six externalizing phenotypes and f...

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 utili...

Historically, researchers have proposed higher-order factors to explicate the structure of psychopathology, including Externalizing, Internalizing, Fear, Distress, Thought Disorder, and a general factor. Despite extensive research in this domain, the underlying structure of psychopathology remains unresolved. Here, we examine several issues in adju...

Longstanding psychological accounts of political conservatism and political extremism posit a foundational role for rigid thoughts, feelings, goals, and behaviors. Critically, these theories rest on a set of auxiliary, implicit hypotheses that can be broadly summarized as follows: rigidity, conservatism, and extremism are conceptually and statistic...

Behaviors and disorders characterized by difficulties with self-regulation, such as problematic substance use, antisocial behavior, and symptoms of attention-deficit/hyperactivity disorder (ADHD), incur high costs for individuals, families, and communities. These externalizing behaviors often appear early in the life course and can have far-reachin...

Proprietary genetic datasets are valuable for boosting the statistical power of genome-wide association studies (GWASs), but their use can restrict investigators from publicly sharing the resulting summary statistics. Although researchers can resort to sharing down-sampled versions that exclude restricted data, down-sampling reduces power and might...

Quantitative, empirical approaches to establishing the structure of psychopathology hold promise to improve on traditional psychiatric classification systems. The Hierarchical Taxonomy of Psychopathology (HiTOP) is a framework that summarizes the substantial and growing body of quantitative evidence on the structure of psychopathology. To achieve i...

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched a...

In this chapter, I offer my perspective on Scott Lilienfeld’s contributions to the field of psychology and on his formative influences, through the lens of our 40-year friendship and 30-year collaboration. In doing so, I hope to illuminate some aspects of Scott’s developmental trajectory that contributed to him becoming the person that so many came...

Clinical psychology is a young science. Despite immense growth over 100+ years, human suffering from mental health conditions remains extensive, and core scientific issues in our field continue to be the subject of ongoing debate. Clinical practice depends on the growth of our research base for elucidating etiology, systematic improvements in provi...

Much research has demonstrated that psychopathology can be described in terms of broad dimensions, representing liability for multiple psychiatric disorders. Broad spectra of psychopathology (e.g., internalizing and externalizing) are increasingly used as targets for research investigating the development, etiology, and course of psychopathology be...

Historically, researchers have proposed higher-order factors to explicate the structure of psychopathology, including Externalizing, Internalizing, Fear, Distress, Thought Disorder, and a general factor. Despite extensive research in this domain, the underlying structure of psychopathology remains unresolved. Herein, we examine several issues in ad...

Substance use disorders (SUDs) are phenotypically and genetically correlated with each other and with other psychological traits characterized by behavioral undercontrol, termed externalizing phenotypes. In this study, we used Genomic Structural Equation Modeling to explore the shared genetic architecture among six externalizing phenotypes and four...

Genome-wide association studies (GWAS) identify genetic variants associated with a trait, regardless of how those variants are associated with the outcome. Characterizing whether variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk. In the current analysis, we used multiva...

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...

The Hierarchical Taxonomy of Psychopathology (HiTOP) is a quantitative nosological system that addresses shortcomings of traditional mental disorder diagnoses, including arbitrary boundaries between psychopathology and normality, frequent disorder co-occurrence, substantial heterogeneity within disorders, and diagnostic unreliability over time and...

This commentary discusses questions and misconceptions about HiTOP raised by Haeffel et al. (2021). We explain what the system classifies and why it is descriptive and atheoretical, highlighting benefits and limitations of this approach. We clarify why the system is organized according to patterns of covariation or comorbidity among signs and sympt...

In this commentary, we discuss questions and misconceptions about the Hierarchical Taxonomy of Psychopathology (HiTOP) raised by Haeffel et al. We explain what the system classifies and why it is descriptive and atheoretical, and we highlight benefits and limitations of this approach. We clarify why the system is organized according to patterns of...

Genetic predispositions and environmental influences both play an important role in adolescent externalizing behavior; however, they are not always independent. To elucidate gene–environment interplay, we examined the interrelationships between externalizing polygenic risk scores, parental knowledge, and peer substance use in impacting adolescent e...

Much research has demonstrated that psychopathology can be described in terms of broad dimensions, representing liability for multiple psychiatric disorders. Broad spectra of psychopathology (e.g., internalizing and externalizing) are increasingly used as targets for research investigating the development, etiology, and course of psychopathology be...

Authoritarianism has been the subject of scientific inquiry for nearly a century, yet the vast majority of authoritarianism research has focused on right-wing authoritarianism. In the present studies, we investigate the nature, structure, and nomological network of left-wing authoritarianism (LWA), a construct famously known as “the Loch Ness Monst...

Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association an...

Importance: Characterizing whether genetic variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk, and, potentially, allows us to design more targeted prevention and interventions. Objective: Employ multivariate methods to tease apart variants associated with problematic alc...

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, par...

The Hierarchical Taxonomy of Psychopathology (HiTOP) is an empirical effort to address limitations of traditional mental disorder diagnoses. These include arbitrary boundaries between disorder and normality, disorder co‐occurrence in the modal case, heterogeneity of presentation within dis­orders, and instability of diagnosis within patients. This...

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, par...

Generations of psychologists have been taught that mental disorder can be carved into discrete categories, each qualitatively different from the others and from normality. This model is now outdated. A preponderance of evidence indicates that (a) individual differences in mental health (health vs. illness) are a matter of degree, not kind, and (b)...

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21566-w

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 clinical practice are therefore limited. The Hierarchical Taxonomy of Psychopathology (HiTOP) consortium proposed a model based on stru...

The present study compared the primary models used in research on the structure of psychopathology (i.e., correlated factor, higher-order, and bifactor models) in terms of structural validity (model fit and factor reliability), longitudinal measurement invariance, concurrent and prospective predictive validity in relation to important outcomes, and...

Dimensions of irritability and defiant behavior, though correlated within the structure of ODD, convey separable developmental risks through adolescence and adulthood. Irritability predicts depression and anxiety, whereas defiant behavior is a precursor to antisocial outcomes. Previously we demonstrated that a bifactor model comprising irritability...

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analy...

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is ge...

Behaviors and disorders related to self-regulation, such as substance use, antisocial conduct, and ADHD, are collectively referred to as externalizing and have a shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5...

Genome-wide association studies (GWAS) have revealed hundreds of genetic loci associated with the vulnerability to major psychiatric disorders, and post-GWAS analyses have shown substantial genetic correlations among these disorders. This evidence supports the existence of a higher-order structure of psychopathology at both the genetic and phenotyp...

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic and calcium signaling pathways and brain-expressed genes, particularly those with high...

Authoritarianism has been the subject of scientific inquiry for nearly a century, yet the vast majority of authoritarianism research has focused on right-wing authoritarianism. In the present studies, we investigate the nature, structure, and nomological network of left-wing authoritarianism (LWA), a construct famously known as “the Loch Ness Monst...

Evidence suggests that the Oxytocin Receptor Gene (OXTR) influences human social cognition and behavior. OXTR has been investigated in relation to antisocial behavior, but studies examining this association have produced varying results in terms of the magnitude and significance of the association as well as which SNPs are implicated. This meta-ana...

The original version of this article inadvertently omitted the word "with" between "Polymorphisms" and "Antisocial" from the title. The title "The Association of Oxytocin Receptor Gene (OXTR) Polymorphisms Antisocial Behavior: A Meta-Analysis" should be "The Association of Oxytocin Receptor Gene (OXTR) Polymorphisms with Antisocial Behavior: A Meta...

The Hierarchical Taxonomy of Psychopathology (HiTOP) is an empirical structural model of psychological symptoms formulated to improve the reliability and validity of clinical assessment. Neurobiology can inform assessments of early risk and intervention strategies, and the HiTOP model has greater potential to interface with neurobiological measures...

Genome wide association studies (GWAS) have revealed hundreds of genetic loci that underlie major psychiatric disorders, and post-GWAS analyses have discovered substantial genetic correlations among these disorders. This suggests these disorders share a common genetic architecture, implying the presence of a higher order structure of psychopatholog...

The study of psychopathic traits in youth is in its nascent stages and the nature and the structure of these traits is still poorly understood. In one of the most comprehensive analyses to date of the construct validity of the widely used Antisocial Processing Screening Device (APSD), we used two independent samples of youth, one community (N = 220...

Genetic discovery in psychiatry and clinical psychology is hindered by suboptimal phenotypic definitions. We argue that the hierarchical, dimensional, and data-driven classification system proposed by the Hierarchical Taxonomy of Psychopathology (HiTOP) consortium provides a more effective approach to identifying genes that underlie mental disorder...

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). ADHD comorbid with DBDs (ADHD+DBDs) is a complex phenotype with a risk component that can be attributed to common genetic variants. Here we report a large GWAS meta-analysis of ADHD+DBDs based on seven cohort...

We advanced several “riskier tests” of the validity of bifactor models of psychopathology, which included that the general and specific psychopathology factors should be reliable and well represented by their respective indicators and that including a general factor should improve on the correlated factor model’s external validity. We compared bifa...

Structural models of psychopathology provide dimensional alternatives to traditional categorical classification systems. Competing models, such as the bifactor and correlated factors models, are typically compared via statistical indices to assess how well each model fits the same data. However, simulation studies have found evidence for probifacto...

In a large sample of youth (N = 942, 51% female), we found support for a 3 correlated factors model of psychopathology that comprised Distress, Fears, and Externalizing factors. Distress was positively associated with Neuroticism, Fears was not associated with Big Five dimensions, and Externalizing was negatively associated with Agreeableness and C...

For more than a century, research on psychopathology has focused on categorical diagnoses. Although this work has produced major discoveries, growing evidence points to the superiority of a dimensional approach to the science of mental illness. Here we outline one such dimensional system-the Hierarchical Taxonomy of Psychopathology (HiTOP)-that is...

We advanced several “riskier tests” of the validity of bifactor models of psychopathology, which included that the p-factor and specific psychopathology factors should be reliable and well-represented by their respective indicators, and that modeling the p-factor should increase the model’s external validity. We compared bifactor and correlated fac...

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals dia...

Background Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common and most heritable childhood-onset neuropsychiatric disorders, characterized by multifaceted genetics. To date, genetic studies of ADHD focused on additive effects only, explaining just a fraction of its heritability. Thus, we aimed at examining parent of origin ef...

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is ge...

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from...

Decades of research into the etiology of conduct disorder (CD) has yet to yield a consensus on the existence of sex differences in underlying genetic and environmental influences. This may be partly due to the failure of many previous studies to make a distinction between non-aggressive and aggressive CD symptoms or test for potential developmental...

Brainstorming diseases Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric...

The latent structure of schizotypy and psychosis-spectrum symptoms remains poorly understood. Furthermore, molecular genetic substrates are poorly defined, largely due to the substantial resources required to collect rich phenotypic data across diverse populations. Sample sizes of phenotypic studies are often insufficient for advanced structural eq...

Background: The developmental propensity model of antisocial behavior posits that several dispositional characteristics of children transact with the environment to influence the likelihood of learning antisocial behavior across development. Specifically, greater dispositional negative emotionality, greater daring, and lower prosociality-operation...

Importance: Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. Objectives: To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify nove...

There is evidence that models of psychopathology specifying a general factor and specific second-order factors fit better than competing structural models. Nonetheless, additional tests are needed to examine the generality and boundaries of the general factor model. In a selected second wave of a cohort study, first-order dimensions of psychopathol...

The past several decades have witnessed a proliferation of research on the dark triad (DT), a set of traits comprising Machiavellianism, narcissism, and psychopathy. The bulk of DT research has been marked by several core assumptions, most notably that each DT construct is a monolithic entity that is clearly separable from its counterpart DT constr...

An adequate understanding of specialized terminology is a prerequisite for the mastery of core concepts across all scientific disciplines, including psychological science. In a previous article (Lilienfeld et al., 2015), we presented an annotated list of 50 widely used psychological terms that should generally be avoided, or at best used judiciousl...

The reliability and validity of traditional taxonomies are limited by arbitrary boundaries between psychopathology and normality, often unclear boundaries between disorders, frequent disorder co-occurrence, heterogeneity within disorders, and diagnostic instability. These taxonomies went beyond evidence available on the structure of psychopathology...

This chapter summarizes issues that are inherent in genetic association studies including those related to genotyping, study design, statistical analysis, and interpretation and application of results in order to guide translation of this expanding area of research into successful health-related applications. Suggestions for current best practices...

We propose a taxonomy of psychopathology based on patterns of shared causal influences identified in a review of multivariate behavior genetic studies that distinguish genetic and environmental influences that are either common to multiple dimensions of psychopathology or unique to each dimension. At the phenotypic level, first-order dimensions are...