Genetic predisposition for enjoyment of amphetamine's effects found to reduce risk of schizophrenia, ADHD

Genetic variants associated with enjoying the effects of d-amphetamine—the active ingredient in Adderall—are also associated with a reduced risk for developing schizophrenia and attention deficit hyperactivity disorder (ADHD), scientists from the University of Chicago reported in the Proceedings of the National Academy of Sciences on April 7.

The results support a long-standing hypothesis that dopamine, the neurotransmitter connected with the euphoric effects of amphetamine, is related to schizophrenia and ADHD.

“Some of the variants that make you like amphetamine also appear to make you less likely to develop schizophrenia and ADHD,” said study leader Abraham Palmer, associate professor of human genetics. “Our study provides new insights into the biology of amphetamine and how it relates to the biology of risk for these psychiatric diseases.”

Palmer and his team previously conducted a genome-wide association study to identify the genetic variants associated with experiencing the euphoric effects of amphetamine, which is thought to affect risk for drug abuse. Almost 400 volunteers were given d-amphetamine in a double-blind, placebo-controlled experiment. They were then asked to report how the drug made them feel, using carefully designed questionnaires.

The researchers measured genetic differences between these subjects at approximately a million sites throughout the genome to identify variations in the DNA code. They assessed the relationships between each of these variations and sensitivity to amphetamine.

Using data from other large-scale studies, the team examined these same variations for possible overlap with psychiatric disorders. Through rigorous statistical testing, they found that an unexpectedly large number of variations were associated with both sensitivity to amphetamine and risk of developing schizophrenia or ADHD. This suggested that these traits are influenced by a common set of genetic variants.

Moreover, a significant proportion of this overlap appeared to be caused by variants that increased enjoyment of the effects of amphetamine, but decreased the risk for both psychiatric diseases.

The researchers performed similar analyses for traits that they did not expect to be related to amphetamine sensitivity, such as height, irritable bowel disease and Parkinson’s disease. In all of these cases they observed no more overlap than would have been expected by chance alone.

“While this approach would not be a useful diagnostic test, we expect that people who like the effects of amphetamine would be slightly less likely to develop schizophrenia and ADHD,” Palmer said, “and people who did not like amphetamine, we would predict, are slightly more likely to develop these diseases.”

“What is particularly striking is that by examining people’s responses for just a few hours after taking a drug, we can identify an underlying genetic propensity that can manifest as a psychiatric disease over the course of a lifetime,” he said.

These results provide unique genetic evidence for the role of dopamine in schizophrenia and ADHD. Schizophrenia is commonly treated using drugs that block dopamine signaling, while ADHD is treated using drugs, including d-amphetamine, that enhance dopamine signaling. Despite opposite treatments, amphetamine-liking variations reduced the risk for developing both diseases, suggesting that dopamine’s role is more complex than previously thought.

The study also offers a new direction for the analysis of a wide range of similar genetic studies, particularly ones with smaller sample sizes. By analyzing the results of those studies for overlap with data from much larger genetic studies, promising genetic variants that would otherwise never stand out among hundreds of thousands of other random variants can be identified.

“Our approach offers a promising new direction for studying complex psychiatric behaviors using the whole-genome approach,” said co-author Harriet de Wit, professor of psychiatry and behavioral neuroscience.

The team plans to further study the variations identified in this study for their functional roles in amphetamine liking, schizophrenia and ADHD. In addition, Palmer hopes to explore genetic predispositions toward liking or disliking other therapeutic drugs, and whether sensitivity to those drugs might also overlap with the diseases for which these drugs are used.

“When we use a drug treatment, we know exactly what systems have been perturbed,” Palmer said. “So when we see overlap for alleles that affect how you respond to drugs and a disease, we can hone in on what those alleles are doing biologically. This is instrumental for translating those results into new treatments and cures, which is the ultimate reason for performing genetic studies of disease.”

The study, “Genetic variation associated with euphorigenic effects of d-amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder,” was supported by the National Institutes of Health. Additional authors include Amy B. Hart, Eric R. Gamazon, Barbara E. Engelhardt, Pamela Sklar, Anna K. Kähler, Christina M. Hultman, Patrick F. Sullivan, Benjamin M. Neale, Stephen V. Faraone, Psychiatric Genomics Consortium: ADHD Subgroup and Nancy J. Cox.

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