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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 3]
 By Charles W. Schmidt // Illustration by Martin O'Neill
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Because mental illnesses are complex, often inherited disorders, scientists have assumed that multiple genes are involved in their cause, each contributing a tiny portion to the total risk. But what if some genes are found to contribute more of the risk? Sklar thinks it's possible, and points to recent discoveries in another complex disorder, age-related macular degeneration (AMD), to bolster her case.
Scientists have found that a large amount of the inherited risk for AMD, the leading cause of blindness in the elderly, depends on a variation in a gene that codes for a protein called complement factor H. One hypothesis is that complement factor H, part of the immune system, may help clear cellular debris from the back of the eye. The theory is that the variation slows this activity, thus contributing to blindness.
In a new study, Sklar and her colleagues are scanning 500,000 gene variants, known as single nucleotide polymorphisms, obtained from a sampling of patients with bipolar disorder. Ideally, the scan will identify critical risk genes that may also offer treatment opportunities. "People used to think all the risk genes had such tiny effects that it would be hopeless to find any with large contributions to the total risk," she says. "The AMD finding shows you can't rule out the possibility that important risk genes do exist. If we can find them, it's likely they'll make more opportune drug targets than genes that contribute comparably smaller risk."
Many other genes are attracting intense scientific scrutiny. There is brain-derived neurotrophic factor (BDNF): Some researchers suspect a variant BDNF gene might prevent hippocampal cells in the brain from functioning normally and possibly increase the risk of depression. Problems with another gene, which codes for catechol-O-methyl transferase (COMT), could interfere with the metabolism of dopamine, increase the risk of schizophrenia and affect the frequency of manic cycles in bipolar disease. And dysbindin, which has been linked to schizophrenia, appears to affect brain synapses related to overall intellectual abilities.
Yet progress is incremental, and conclusive data linking any risk gene to disease is elusive. More research is needed to identify new genes, to replicate existing evidence in larger population samples and to tie implicated genes into broad disease processes, says Douglas Levinson, professor of psychiatry at the University of Pennsylvania School of Medicine. And as the research moves forward, however slowly, the tentative links between genes and mental illness could solidify into more definitive diagnostic tools that might give the physicians of future Faith Reidenbachs a better understanding of exactly what ails their patients.
 Dossier
1. "Genetics of Psychiatric Disorders," Nature Neuroscience, June 2005. Editorial describing how new genetic research methods are being applied to studies of mental illness.
2. "Gene Hunting," 2001, www.nimh.nih.gov/publicat/huntgene.cfm Brief overview, for a lay audience, of methods used to identify genes associated with mental illness.
3. "Meta-Analysis in Psychiatric Genetics," by Douglas F. Levinson, Current Psychiatry Reports, April 2005. Describes gene-identification methods—emphasizing linkage and association studies—used in research on bipolar disorder and schizophrenia.
4. "Support for Involvement of Neuregulin 1 in Schizophrenia Pathophysiology," by Pamela Sklar et al, Molecular Psychiatry, April 2005. Research supporting neuregulin 1's suspected role in schizophrenia.
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