Breaking Bad Genetics

Some of us may have heard people say, “Addiction runs in my family.” And it’s common knowledge that substance abuse is driven by genetic, as well as environmental factors. It’s only recently, though, that a group of researchers from Boston University School of Medicine have identified a gene that demonstrates a causal relationship to addiction – specifically, to methamphetamine sensitivity (1).

“Both genes and environment can exert independent and interactive influences on an individual’s risk for developing an addiction throughout life,” explains corresponding author Camron Bryant. “Gene discovery is one important piece of the puzzle in understanding the neurobiological adaptations that confer risk versus resistance to the addictions throughout development and into adulthood.” Bryant and his colleagues employed an unbiased, discovery-based approach called quantitative trait locus (QTL) mapping in mice; they sought broad chromosomal regions causally associated with variations in sensitivity to the methamphetamine locomotor stimulant response – a behavior is associated with activation of the dopamine reward circuitry in the brain. “We honed in on a particular region of a chromosome by using a ‘fine mapping’ approach to identify the smallest possible region necessary for differential drug responding. The region we identified contained only two protein-coding genes, which we mutated to identify the causal factor.” The gene Bryant and his colleagues ultimately discovered is called heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1), which codes for an RNA-binding protein that regulates hundreds of genes in the brain.

“An obvious next step is to determine whether or not this novel factor is genetically associated with methamphetamine addiction in humans,” says Bryant. “That would strengthen the impact of our findings and could have implications for prescribing psychostimulant drugs like Adderall or Ritalin, which have similar molecular mechanisms of action to methamphetamine.” At the moment, the researchers are developing the tools to identify the brain region-specific RNA targets of hnRNP H1 and assessing its contribution to behavioral traits more closely aligned with addiction, including conditioned drug reward and self-administration of drugs of abuse. They are also extending their findings to other disease models known to be associated with dysfunction of RNA binding proteins. Gene expression analysis indicates a role in dopaminergic neuron development – meaning that hnRNP H1 may play a role not only in addiction, but in neurological disorders like ADHD, schizophrenia, and Parkinson’s disease.