Projects

UW Gene-Environment Study

The primary purpose of the study is to examine how neurobiological (i.e., temperament, genetics) and environmental factors independently and jointly influence variation in early childhood self-control and reward sensitivity, two key constructs within the NIMH Research Domains Criteria (RDoC). Self-control and reward sensitivity are highly heritable, multifactorial constructs with cross-cutting associations to the externalizing disorders, such as oppositional defiant disorder, conduct disorder, and attention-deficit/hyperactivity disorder. Yet, not all children with deficiencies in these traits develop externalizing problems. The current study utilizes a developmental psychopathology framework to examine the neurobiological and environmental factors that underlie these traits, and to determine how variation across these factors may uniquely “set the stage” for behavioral development.

 

Add Health Study

Our project uses data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) (http://www.cpc.unc.edu/projects/addhealth) to investigate the independent and interactive roles of genes and environments on antisocial behavior trajectories, from adolescence to adulthood. Our specific aim is to test the theory that certain genes will interact not only with negative environmental risk factors, but also with enriched/positive environmental factors (i.e., neighborhood characteristics, religiosity, social support, relationships with parents) to predict individual variation in antisocial behavior trajectories.

Key collaborators: Ashley Wazana, M.D. (Psychiatry, McGill University), Alexia Jolicoeur-Martineau (Statistics & Artificial Intelligence, McGill University), Ezster Szekely, Ph.D. (Psychiatry, McGill University), Jonathan Martinez, Ph.D. (Psychology, California State University-Northridge), Qiongshi Lu, Ph.D. (Biostatistics & Medical Informatics, UW-Madison)

 

Wisconsin Longitudinal Study (WLS)

The Wisconsin Longitudinal Study (WLS) is a long-term study of a random sample of 10,317 men and women who graduated from Wisconsin high schools in 1957. The WLS provides an opportunity to study the life course, intergenerational transfers and relationships, family functioning, physical and mental health and well-being, and morbidity and mortality from late adolescence through 2011. WLS data also cover social background, youthful aspirations, schooling, military service, labor market experiences, family characteristics and events, social participation, psychological characteristics and retirement. The goal of this study is to test how genetic factors interact with dimensions of social environments (i.e., support and stress) on health and behavioral outcomes. For more information about WLS: https://www.ssc.wisc.edu/wlsresearch/

Key collaborators: Jan Greenberg, Ph.D. (Social Work, UW-Madison),  Jinkuk Hong, Ph.D. (Waisman Center, UW-Madison), Qiongshi Lu, Ph.D. (Biostatistics & Medical Informatics, UW-Madison),  Marsha Mailick, Ph.D. (Social Work, UW-Madison)

 

Neurogenetics of ADHD Study

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, neurodevelopmental disorder with a high prevalence in the population, affecting between 8-12% of children and adolescents worldwide. Genetic influences account for nearly 80% of its overall etiology, yet its precise genetic architecture remains poorly characterized. The ascendency of genome-wide association studies (GWAS) for ADHD have led to new discoveries with respect to the genes involved in its pathogenesis, but these studies provide no direct evidence about gene function, including its effect on the brain and subsequent behavior. Linking genome-wide signals with neural function is crucial for understanding the biological mechanisms of risk for ADHD and may lead to novel targets for intervention. This study integrates genomics, bioinformatics data and neuroimaging techniques to precisely characterize the brain mechanisms underlying genome-wide risk for ADHD.

Key collaborators: Ryan Herringa, M.D., Ph.D. (Psychiatry, UW-Madison) and Qiongshi Lu, Ph.D. (Biostatistics & Medical Informatics, UW-Madison)

 

Genetics of a General Factor in Psychopathology Study

Psychiatric disorders tend to co-occur. This phenomenon (i.e., “comorbidity”) is a hallmark of the Diagnostic and Statistical Manual of Mental Disorders and an especially major issue in the emerging field of psychiatric genetics, since it greatly complicates our search for specific genes for specific disorders. There is increasing evidence that psychopathology may have a hierarchical rather than categorical taxonomy, such that a single major source of risk may be shared across all of the disorders and that other risk factors may contribute to the development of each specific disorder. This study uses individual genotype and phenotype data from the Neurodevelopmental Genomics: Trajectories of Complex Phenotypes (i.e., PNC) dataset to characterize the genetic variation underlying the general risk for psychopathology (i.e., the general factor) and specific risk for each disorder (specific factors).

Key collaborators: Qiongshi Lu, Ph.D. (Biostatistics & Medical Informatics, UW-Madison)

 

The Neurogenetics of Co-Occurring Autism Spectrum Disorder and ADHD

Autism spectrum disorder (ASD) is highly heritable neurodevelopmental disorder. Genetic influences account for between 64-91% of the variance in childhood ASD. Yet, little is known about how specific genes (i.e. common SNPs) map onto neural substrates that have been theorized to underlie its development. Furthermore, ASD frequently co-occurs with other neurodevelopmental disorders, co-occurring with attention-deficit/hyperactivity disorder (ADHD) at a rate of 28-87%. And yet, the biological mechanisms that underlie their frequent comorbidity has also been unexplored. Our lack of knowledge regarding the mechanisms underlying this comorbidity is particularly problematic from a clinical perspective; when compared to individuals with either ADHD or ASD alone, youths with both ASD and ADHD are more likely to be prescribed psychotropic medications such as risperidone and aripiprazole, which are not intended to treat either of these disorders. There is an urgent need to correct this gap in knowledge because co-occurring ASD and ADHD may have distinct genetic and neurobiological underpinnings compared to ASD or ADHD alone. In line with NICHD priorities to understand the complexity of comorbid symptoms, our goal is to identify the neurobiological mechanisms of genetic risk for ASD alone, ADHD alone, and their comorbid presentation (i.e., ASD+ADHD). As a first step toward accomplishing this goal, our first main objective is to test and subsequently validate innovative polygenic score models that incorporate statistical and a bioinformatic information to precisely predict membership into one of these three clinical phenotypes. This will be demonstrated in large population datasets (Aim 1) and in a well-characterized clinically representative dataset (Aim 2). The second main objective is to investigate the neurobiological mechanism underlying these polygenic score associations with neurodevelopmental phenotypes by testing whether they are biologically mediated by a key and vastly understudied brain structure in the brainstem (Aim 3).

Key Collaborators: Brittany Travers, Ph.D. (Kinesiology, UW-Madison) and Qiongshi Lu, Ph.D. (Biostatistics & Medical Informatics, UW-Madison)