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| Archive : Fall 2005 |
How Mental Illness Researchers are Honing in on a Moving Target:
Browsing the human genome for markers // Canvassing Icelanders, Germans and Han Chinese // Studying weak brain circuits and undersize amygdalas // Sorting nature from nurture.
The Scarlet Gene [page 2]
 By Charles W. Schmidt // Illustration by Martin O'Neill
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"This finding corresponds to what clinicians have thought for centuries," says Patrick Sullivan, professor of psychiatry at the University of North Carolina at Chapel Hill School of Medicine. "It suggests depression isn't caused by bad events per se, but rather by an interaction between genes and environment." Sullivan cautions, however, that the data are not yet complete. What Caspi and Moffitt didn't explain was how the genetic variation induces this effect. That piece of the puzzle had come a year earlier, from Daniel Weinberger, who directs the Genes, Cognition, and Psychosis Program at the National Institute of Mental Health (NIMH).
Weinberger suspected that those who inherit the variant transporter, and who were associated with more anxiety and fearfulness in earlier studies, would exhibit greater neural activity in the amygdala, the part of the brain that processes fear. So he and colleague Ahmad Hariri divided volunteers into two groups—one with the "short" variant and one without—and compared (using functional magnetic resonance imaging, which generates snapshots of the brain in action) how their amygdala responses differed when they were shown pictures of fearful faces, a common method for triggering an amygdala response.
Sure enough, Weinberger and his colleagues discovered that viewing the pictures produced especially pronounced amygdala activity in subjects with the variant transporter. They then deduced that the variant's effect on the amygdala makes people more likely to view the world as menacing. Life stresses, they reasoned, may be amplified to the point of inducing depression.
Weinberger's research group followed up with findings published in the June 8, 2005, issue of Nature Neuroscience. They scrutinized circuits connecting the amygdala to the cingulate, an emotion-dampening center near the front of the brain. Subjects with the "short" transporter variant had a smaller amygdala and cingulate, both critical for processing negative emotion. They also had weaker brain circuits, and that apparently interferes with the cingulate's ability to stop fear triggered by the amygdala.
"All this is a focus of intense research," says Andreas Meyer-Lindenberg, chief of the Unit for Systems Neuroscience in Psychiatry at the NIMH and an author of the Nature Neuroscience article. "Studies show that if you alter serotonin transmission in newborn mice, you can make them anxious for life. And though we can't verify it from our data, we also think there's a highly causal relationship between changes in serotonin metabolism and the smaller size of both the amygdala and the cingulate and a weaker connection between them."
Serotonin pathways, targeted by many drugs that treat depression, and the genes that control them have a long history in research. But what of the many other genes that may also bear on mental illness? The hunt is on, spurred by recent advances in genomics, which draws biological insights from studies of gene sequences and their variations.
Scientists often start by looking for genetic inheritance patterns among family members with a history of a particular illness. If successful, such analyses point to DNA regions that may correlate with a given disorder. For instance, if several relatives suffer from depression, researchers can sort through their DNA hoping to find regions they all share—in higher proportions than would be expected given their relatedness—where a variant disease gene might lie. Then they try to isolate variations in the gene (or genes) that appear to promote disease susceptibility.
Consider neuregulin 1, one of several genes suspected of playing a role in schizophrenia. Neuregulin 1 is an enormous gene, more than a million base pairs long, that produces at least 15 "signaling proteins," which facilitate cell-to-cell communication in various tissues, including the brain. In 2002, deCODE Genetics, a biopharmaceutical company in Reykjavik, Iceland, reported evidence of a connection between neuregulin 1 and schizophrenia. The evidence emerged from a linkage study of Icelandic families that showed that schizophrenia correlated with an area on the eighth of the 23 pairs of human chromosomes. More refined studies pointed to neuregulin 1 as a potential risk factor.
Further studies by Pamela Sklar, associate director of the Psychiatric and Neurodevelopmental Genetics Unit in the Center for Human Genetic Research at the Massachusetts General Hospital, have suggested that other parts of the gene might also be involved. A neuroscientist, geneticist and clinical psychiatrist, Sklar plans to break the huge neuregulin 1 gene into individual chunks for careful study. "We don't know yet where the actual defect is," she says. "If we can narrow our search to one part of the gene, then we can really focus attention on that area to see if something there is linked to the disease."
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