Careers Up Close: Rohan Palmer on Genetics and Substance Use

Image above: Author Rohan Palmer, Emory University

Emory University psychological scientist Rohan Palmer is engaged in cutting-edge research on the genetic and environmental factors that leave some people vulnerable to substance dependency. He is also investigating whether genome-related outcomes can be generalized across populations.  

What led to your scientific interest in the combinations of genetic variants that confer susceptibility to dependance on alcohol and other drugs? 

I became interested in molecular genetic studies of substance addiction during my first year of postdoctoral training. My graduate training in quantitative and statistical genetics had focused on using twins and their siblings to infer how the misuse of substances occurred. The study suggested that relatives resemble each other in their substance use because of genetic and (sometimes) common environmental factors. During graduate school, I was fascinated by genome-wide association attempts to find the genetic loci, but I was also disappointed by the lack of a theoretical framework that captured the network of brain structures and neurotransmitter systems involved in substance addiction. As I was limited by the amount of available genetically informed samples accessible to me, I sought out training to fill this gap in the literature.  

I started to expand my program of research to encompass molecular studies with the goal of capturing sets of genes that underlie the neuronal response to substances of abuse. An interesting observation was that there was limited evidence for an “addiction gene.” As I began to consider the emergent properties of the human genomes from a systems perspective, I realized that I couldn’t just study alcohol and other drugs because genetic loci did so much more than manifest a single behavior. (DNA variation not only affects variability in proteins but also in their regulation; further, a protein’s effects depend on when it is expressed and in which tissue(s).) Learning all of this led me to investigate other aspects of behavior, such as novelty seeking and depression, that serve as risk factors for addiction susceptibility and indicators of drug addiction. I cannot imagine being the researcher I am today without having realized the importance of interdisciplinary research and theoretical perspectives to investigate the nature of comorbid psychopathologies. 

Since my early work, my collaborators and I have characterized the polygenetic liability of drug dependence vulnerability using whole genome data, which are rarely examined together in the genetic literature. But I realize we are still just touching the tip of the iceberg. Many of these studies have relied upon data from individuals of European ancestry and thus fail to consider the social construct of race beyond ancestral benefits. Much work is still needed to understand these effects globally in men and women who have different lived experiences. 

You study genetic and environmental factors that may contribute to substance use disorders—what has your research shown so far? Do environmental or genetic factors appear to be more important? How about their interplay? 

To date, our research has shown that there are numerous genes, genetic loci, and environmental situations, such as the amount of emotional support, that are involved in starting to use and misuse substances. This contradicts earlier assumptions that there may be just one or a few genes involved in substance use disorders. Most interestingly, we have also seen that genetic factors often reside outside of genes—instead they are in the regions that regulate them. This has led to a shift toward studies that examine how genes may be perturbed in biological pathways in tissues of interest. 

Genetic and environmental factors are equally important, especially considering the variation in our DNA that affects substance use also plays a significant role in other traits like reward seeking, impulsivity, and neuroticism. The example of personality disorders commonly co-occurring with substance use disorders highlights how forms of psychotherapy that enhance how we manage our environment (e.g., stress coping) can minimize the onset and severity of substance use problems. Often more than we realize, the genetic and environmental factors are working together to influence our behaviors, but discerning these effects is not so simple—what might appear to be a correlation between two behaviors may be the result of shared genetic and/or environmental factors. The pattern of associations we have found depends on the age of participants in the sample and the measures of behavior and environment under study. 

Do you find that different factors contribute differently to substance use and substance use disorders? That is, are there factors that appear to make substance use become a disorder?   

We have found that there are overlapping genetic factors that appear to influence both alcohol use and alcohol use disorder. There also appear to be effects from genetic factors that are unique to the types of substance involvement. We are still working to understand whether these effects are more than just qualitatively different.  

You have noted that much of the work that has been done in genetics research, including your own, does not generalize to the populations with the greatest need, largely owing to disparities in research participation. What can you share about how the MAPme project, or any other projects that you’re involved with, will help to close this gap? 

There is a tremendous need for greater representation of marginalized, underserved, and/or underrepresented populations in genetics and genomics research. Concerns arising from existing genome-wide association studies (GWAS) are whether the outcomes being studied can be generalized across populations and sociodemographic and ancestral groupings. Likewise, we have more to learn about whether the lived experiences across these groupings share the same combination of genetic and environmental factors and their interplay. To overcome the problem of making erroneous conclusions when trying to generalize from “white majority” studies, myself and others have been working to diversify the sampling pool and identify and attempt to correct for measurement noninvariance. 

The MAPme Study is one of several others, such as Spit4Science (at Virginia Commonwealth University) and the Pathways to College Health Study (at Arizona State University), that combines DNA genotyping with online assessments in a longitudinal design. By characterizing behaviors across different demographic groupings using extensive phenotyping, we seek to better characterize the social environment and behaviors that influence emotional well-being and health behaviors like substance misuse. I believe these designs are well-suited to complement the large-scale GWAS approaches like All of Us, Adolescent Brain and Cognitive Development (ABCD), Human Heredity and Health in Africa (H3Africa), Genome Asia, and GWAS consortia (e.g., Latina American Genomics Consortium) that have the greatest potential to capture the most easily attainable genetic effects. More specifically, we will be able to leverage any observed effects using more theoretically driven models that provide important context about how genetic factors operate in different environmental situations. 

How would you apply your research to the treatment of substance use disorders? 

That is a fantastic question and one that we have recently begun to pursue in the laboratory using multi-omic and cross-species approaches. An interesting aspect of GWAS is that much of the genetic loci associated with a disease reside outside of the protein coding sequences. These variants may be linked to genes and have functional consequences on proteins by affecting whether or not the protein is produced, or whether the same protein molecule is generated or operates at the same capacity. In essence, our DNA tells us one part of the story about how our body may be operating. The other half is how cells respond to substances of abuse by altering levels of proteins.  

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The lab has recently developed a drug repurposing pipeline that is anchored in how human brains’ (and the brains of model organisms) protein levels are affected by substances of abuse. Specifically, we are looking at the gene expression profile of the brain and comparing it to the gene expression profile of neuronal cells under the direct influence of different compounds. The great thing about this approach is that it has the potential to identify pharmacological therapies for substance use disorders. We applied this to cocaine and found that there are several compounds, such as Ibrutinib—a Bruton’s tyrosine kinase (BTK) inhibitor—that is critical for B-cell survival and proliferation. Notably, other BTK inhibitors have been shown to reduce alcohol intake in mice that are selectively bred to engage in binge-like drinking. More recently, we have been working to improve this while pursuing funding for in vivo testing of our top-ranked drug candidates. We have also been conducting proof of principle studies for other psychiatric diseases and substance use disorders using other compounds, including those undergoing clinical trials. 

What are your plans for the future?  

In addition to our drug repurposing efforts, my collaborators and I are very interested in integrative studies to identify and understand how genetic factors operate, particularly in different sociodemographic and behavioral contexts. For example, we are in the process of collecting behavioral and genetic data on drinkers to better understand compulsive alcohol use in humans. I am also collaborating with experts in psychology, psychiatry, and genetics to identify combinations of genetic, epigenetic, and social environmental factors that confer risk for mental health disorders. We are currently focusing on African Americans with a history of trauma, but our next step is to understand how cultural, physiological, and sociodemographic characteristics shape these associations within African American men and women, as well as other racial/ethnic groupings. Additional details on these and our other studies are available on the lab website. I am always happy to collaborate with others who have similar interests or want to incorporate genetic studies into their program of research.  

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