Genes for 'Liking' Amphetamine Lower Schizophrenia, ADHD Risk

Deborah Brauser

April 10, 2014

Genetic variants that boost sensitivity to the euphoric effects of d-amphetamine may reduce the risk of developing schizophrenia or attention-deficit/hyperactivity disorder (ADHD), new research suggests.

The analysis, which included nearly 400 healthy volunteers plus data from 220,000 individuals from other studies, showed that those who had an excess of alleles that increased sensitivity to the euphoric effects of amphetamine were also less susceptible to developing schizophrenia or ADHD.

"This is a really exciting finding because, while we can't point to the specific genes that lead to those shared risks for the 2 phenotypes, it does say that something is going on with dopaminergic signaling in the brain," Abraham A. Palmer, PhD, associate professor in the Department of Human Genetics at the University of Chicago, told Medscape Medical News.

However, he noted that the 2 disorders are treated oppositely, with dopamine receptor agonists used to treat ADHD and dopaminergic antagonists/blockers used for schizophrenia ― suggesting that the role of dopamine is more complex than commonly thought.

"So this finding was surprising. I had imagined that alleles that made you more likely to develop schizophrenia or ADHD would be oppositely loaded; they would be in opposition to each other. But that's not what we saw. Variants that made you like amphetamine more were protective against both disorders," said Dr. Palmer.

He did note that their testing approach is not likely to become a diagnostic tool for clinicians in the near future.

Dr. Abraham Palmer

"As with most other genetic tests, we can't trust that genotyping will do as good a job at predicting risk for developing 1 of these diseases as we can get from taking a good family history," he said. "I do, though, think it will be valuable for identifying on a functional level how some alleles are influencing risk for these diseases."

The study was published online April 7 in the Proceedings of the National Academy of Sciences Early Edition.

Large Number of SNPs

In the original genome-wide association study (GWAS) conducted by the investigators and reported in 2013, 381 healthy volunteers were given 10-mg or 20-mg doses of d-amphetamine or placebo during 3 office visits.

The self-reported Profile of Mood States, Drug Effects Questionnaire, and Addiction Research Center Inventory were administered at each visit to ask the participants several questions, including how the capsule made them feel.

Blood samples were also taken for DNA testing.

Genetic differences between the participants were measured "at approximately a million sites throughout the genome to identify variations in the DNA code known as single nucleotide polymorphisms, or SNPs," explained the researchers in a release. Associations between these SNPs and amphetamine sensitivity were then assessed.

For the current analysis, data from 7 other large-scale GWAS studies were also included to examine overlapping associations with various psychiatric disorders.

These included the PGCI Schizophrenia (9394 European patients with schizophrenia and 12,462 without), PGCI ADHD (total n = 5415), and PGCI Bipolar Disorder (n = 16,731) studies.

"We looked to schizophrenia and ADHD particularly because both of these disorders are treated with dopaminergic drugs," said Dr. Palmer.

Results showed that "an unexpectedly large number of SNPs" were linked to amphetamine sensitivity and risk of developing schizophrenia or ADHD, suggesting that "these traits are influenced by a common set of genetic variants," report the investigators.

Much of this overlapping appeared to be caused by genetic variants that increase the enjoyment of amphetamine's effects while also protecting against schizophrenia (P ≤ .05) or ADHD (P ≤ .01).

In addition, a subset of enriched SNPs was found to be shared by all 3 phenotypes: amphetamine response and both psychiatric disorders.

An overall significant enrichment of SNPs associated with bipolar disorder was not observed for those with a euphoric response to d-amphetamine.

"However, when we stratified SNPs by concordant vs discordant, we…observed a significant enrichment of discordant SNPs at both the P ≤ 0.01 and P ≤ 0.05 thresholds," write the researchers.

Discordant SNPs were defined as increased amphetamine response and decreased risk for the disorder, whereas concordant SNPs were characterized by an increased amphetamine response and increased risk.

Further analysis showed no significant overlapping SNPs between amphetamine sensitivity and Parkinson's disease, irritable bowel disease, or height.

A Real Advance

Overall, the findings show that "the genetic susceptibility to the euphoric effects of d-amphetamine also influences the genetic predisposition to schizophrenia and…ADHD," summarize the investigators.

"Interestingly, our results [also] suggest that insensitivity to a drug that is used to treat ADHD might be a genetic risk factor for ADHD; however, it is important to note that we examined sensitivity to the euphoric effects of amphetamine and not sensitivity to its therapeutic effects."

They add that a puzzling finding was the enrichment of protective alleles for both disorders among the association with increased amphetamine response, especially because they are commonly believed to have different types of dopamine dysregulation.

"This was the surprise of the paper and one of those things that makes it exciting to do research. You genuinely don't know what you're going to get until you start looking into it," laughed Dr. Palmer.

"However, I think this is consistent with both epidemiologic data and some recent genetic data that have looked at whether there are shared genetic risks. We have known for a few decades that in families that have several individuals with schizophrenia, you also see a greater proportion of a whole range of other psychiatric diseases," he added.

"And I think our finding represents a real advance in the way that we can think about these disorders."

The study authors have reported no relevant financial relationships.

Proc Natl Acad Sci. Published online April 7, 2014. Full article

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