"A combination of variants turned out to have a high effect on the risk of dying. That is called epistasis a gene-gene-environment interaction that is seen only when there is that extra stimulus, in this case the cocaine," Sadee said. "It's a three-way system, which is incredibly complex unless you know beforehand that these variables are all related to each other."
Sadee said consideration of how gene-gene-environment interactions affect the impact of single genes could help solve the mystery of "missing heritability." Scientists know that genes are behind the causes of many diseases and conditions, but to date have been unable to document the complete genetic history of any given disease.
More immediately, what he has discovered about these variants is likely to increase understanding of numerous psychiatric disorders and improve the effectiveness of medical therapies for these problems. Dopamine-related conditions include attention deficit-hyperactivity disorder, bipolar disorder, phobias, anxiety and schizophrenia.
"The gene-gene interaction that we've reported here, eliciting what might be a 'perfect dopamine storm' under cocaine stimulation, could well contribute to other conditions and affect response to drugs such as antipsychotics and amphetamines," Sadee said.
Clinical studies led by his lab so far suggest that gene-gene interactions occurring without an environmental stimulus such as cocaine do appear to help predict response to certain medications.
He is also extending the research to a handful of other genes that affect signaling in the brain.
"Each gene gives us new combinations, each one has novel variants that can be tested in this way. And they may be considered normal variations they're not associated with a disease process, but if there are multiple variants together, they may
|Contact: Wolfgang Sadee|
Ohio State University