Biology subjects

Waldman, I. D.

Publications and source records attributed to Waldman, I. D..

4 recordsLinked to original sources

bioRxiv2022

A Multivariate Approach to Understanding the Genetic Overlap between Externalizing Phenotypes and Substance Use Disorders

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 SUDs used in two previous multivariate GWAS of an externalizing and an addiction risk factor, respectively. Using a preregistered set of criteria, we first evaluated the performance of five confirmatory factor analytic models, including a common factor model, alternative parameterizations of two-factor structures, and a bifactor model. We used a combination of model fit, factor reliability, and model characteristics to adjudicate among the models. We next explored the genetic correlations between factors identified in these models and other relevant psychological traits. We found that a common factor model, in which all externalizing phenotypes and SUDs were influenced by a single dimension of genetic risk best characterized the relationships among our phenotypes. Although two two-factor models also performed well, we found that the factors in those models were very highly correlated with each other (rgS > .87) and similarly genetically correlated with external criteria, suggesting they did not represent meaningfully distinct dimensions. Results from this study can be used to inform future efforts to characterize genetic liability for broad externalizing as well as specific externalizing phenotypes.

genetics↗

bioRxiv2020

Multivariate genomic analysis of 1.5 million people identifies genes related to addiction, antisocial behavior, and health

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 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The identified loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results captures variation in a broad range of behavioral and medical outcomes that were not part of our genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions, and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental condition.

genetics↗

bioRxiv2019

Identification of risk variants and characterization of the polygenic architecture of disruptive behavior disorders in the context of ADHD

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 cohorts in total including 3,802 cases and 31,305 controls. Three genome-wide significant loci were identified on chromosomes 1, 7, and 11. A GWAS meta-analysis including a Chinese cohort supported the locus on chromosome 11 to be a strong risk locus for ADHD+DBDs across European and Chinese ancestries (rs7118422, P=3.15x10-10, OR=1.17). This locus was not associated with ADHD without DBDs in a secondary GWAS of 13,583 ADHD cases and 22,314 controls, suggesting that the locus is a specific risk locus for the comorbid phenotype.\n\nWe found a higher SNP heritability for ADHD+DBDs (h2SNP =0.34) when compared to ADHD without DBDs (h2SNP =0.20). Genetic correlations of ADHD+DBDs with aggressive (rg =0.81) and anti-social behaviors (rg=0.82) were high, and polygenic risk score analyses revealed a significant increased burden of variants associated with ADHD and aggression in individuals with ADHD+DBDs compared to ADHD without DBDs. Our results suggests that ADHD+DBDs represent a more severe phenotype with respect to the genetic risk load than ADHD without DBDs, in line with previous studies, and that the risk load to some extent can be explained by variants associated with aggressive behavior.

genomics↗

bioRxiv2018

Testing Structural Models of Psychopathology at the Genomic Level

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 phenotypic levels. Despite recent efforts by collaborative consortia such as the Hierarchical Taxonomy of Psychopathology (HiTOP), this structure remains unclear. In this study, we tested multiple alternative structural models of psychopathology at the genomic level, using the genetic correlations among fourteen psychiatric disorders and related psychological traits estimated from GWAS summary statistics. The best-fitting model included four correlated higher-order factors - externalizing, internalizing, thought problems, and neurodevelopmental disorders - which showed distinct patterns of genetic correlations with external validity variables and accounted for substantial genetic variance in their constituent disorders. A bifactor model including a general factor of psychopathology as well as the four specific factors fit worse than the above model. Several model modifications were tested to explore the placement of some disorders - such as bipolar disorder, obsessive-compulsive disorder, and eating disorders - within the broader psychopathology structure. The best-fitting model indicated that eating disorders and obsessive-compulsive disorder, on the one hand, and bipolar disorder and schizophrenia, on the other, load together on the same thought problems factor. These findings provide support for several of the HiTOP higher-order dimensions and suggest a similar structure of psychopathology at the genomic and phenotypic levels.

genomics↗