The Genetics of Normal

schizophrenia_pet_scanIn the 11 years since the blueprint of human life was decoded by the Human Genome Project, much of the focus has been on when those instructions fail. Scientists have used our newfound genetic knowledge to look for the roots of common and rare diseases, the gene or genes that can increase the risk of everything from heart disease to cancer to asthma. But setting the stage for future illness is not the purpose of genes, of course. By coding for the proteins that make up the body and brain, genes lay the foundation for everything we do, feel, and probably even think.

Like the study of disease, genetic studies of human behavior have mostly focused on the abnormal – the targets of psychiatry. Mental illnesses such as schizophrenia, depression, and drug addiction have been the subjects of genetic hunts, known as genome wide association studies, where the ill are compared to controls to reveal genes that might be involved in the a particular disorder. As with diseases in the rest of the body, psychiatric disorders have mostly resisted easy genetic explanations – only a small percentage of schizophrenia, for instance, has been traced to genetic causes.

A more useful, but also vastly more complicated, approach might be to study not the binary comparison of healthy vs. sick, but the whole spectrum of human behavior. For example, rather than just looking at those with extreme enough depression symptoms for a clinical diagnosis and those who don’t, scientists could look at genes in subjects who are rarely, mildly, or frequently affected by depression, as well as those on the extremes. Such analyses may get closer to the genes and brain structures that control human behavior, both in everyday life and when it breaks down.

These types of experiments have caught the imagination of Abraham Palmer, assistant professor of human genetics at the Medical Center. In collaboration with the laboratory of Harriet de Wit, professor of psychiatry, Palmer has started to look at the behavioral trait of impulsivity, which has been associated with attention deficit disorder and predisposition to drug abuse.

“We’re coming at it from a tradition that’s very psychology, drug abuse-based, but we’re really interested in asking questions that get at the broadest range possible of behaviors,” Palmer said. “These are continuous traits that everybody in the population will have some value for. We’re not talking about it exclusively from a disease perspective. These are healthy people coming in.”

Palmer used Donald Rumsfeld’s infamous quote about known knowns, known unknowns, and unknown unknowns, to illustrate how studies of genes and behavior have classically been limited by the tunnel vision of previous knowledge. If a particular gene is already known to play a role in a behavior, scientists can study how individual variants in that gene correspond to behavior. In one such project, Palmer was part of a team that looked at the D2 dopamine receptor – a neurotransmitter receptor linked with the response to drugs of abuse – and impulsive decision-making.

Volunteers came to the laboratory and performed a “stop task,” a common psychology test. The subject is trained to look for a “go signal” and start hitting a certain keyboard key as quickly as possible until the “stop signal” sounds. The delay between the go and stop signals is steadily decreased with each round, and the ability of the subject to stop on time is measured. Researchers then compared their D2 genotype to their behavioral score, and found a link between different D2 variants and more “impulsive” results on the stop task.

These results help researchers study possible genetic predisposition for drug abuse or addition. But Palmer said he wants to expand the search beyond genes that are already implicated in behaviors and beyond psychiatric conditions.

“We’ve mostly looked at candidate genes, genes where we had reason to think it might modulate a behavior,” Palmer said. “But the more interesting question, if you had a sufficiently large sample and enough power, is to say let’s go at this with a blank state, let’s look at all the polymorphisms in a genome and pull out novel things maybe in genes we had never thought to be related to these processes.”

This kind of study would require thousands of subjects to build enough statistical power to identify previously undiscovered variants. Bringing that many people into the laboratory for experiments and obtaining full genome sequences for them all would be absurdly expensive. So Palmer is proposing a new kind of psychiatric study, able to be conducted from the comfort of a subject’s own home. If the subject has already been genotyped, either as part of a study of some disease, or through a personal genomics service like 23andme, the more expensive genetic data will already be available. Subjects could then be asked to take simple behavioral tests in exchange for something like a $25 gift certificate.

“We can basically give them a website and they go there and get applets to run on their local computer, where they can do tasks locally and then the data gets sent back to our server,” Palmer said. “For a million dollar budget, you can get 40,000 people. That’s a powerful sample for doing a genome-wide analysis where you don’t come at it with preconceived notions of what are the important genes. Instead, you get completely novel insights about what are the genetic predictors of these kinds of behaviors.”

The discovery of new genetic associations can suggest new biological explanations for behavior, in both healthy and unhealthy flavors. Combined with neuro-imaging techniques, scientists can get new clues on what brain regions, neurotransmitters, and networks are involved in processes such as emotion, decision-making, and personality. Once the basis for those behaviors is better understood, ideas about how to treat mental illnesses will surely follow. The key to fixing abnormal may lie in the normal.

“We’ve got a black box here, and if we started to have genes that drop into the middle of this system, we’d get at brain regions, get at networks of signaling pathways and regulation pathways that weren’t previously known,” Palmer said. “The genetics has the potential to give us huge insights.”

=====

Hamidovic, A., Dlugos, A., Skol, A., Palmer, A., & de Wit, H. (2009). Evaluation of genetic variability in the dopamine receptor D2 in relation to behavioral inhibition and impulsivity/sensation seeking: An exploratory study with d-amphetamine in healthy participants. Experimental and Clinical Psychopharmacology, 17 (6), 374-383 DOI: 10.1037/a0017840

About Rob Mitchum (523 Articles)
Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.
%d bloggers like this: