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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

By Charles Schmidt // Illustration by Martin O'Neill // Fall 2005
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Mental illness gene markers

I n December 1979, Faith Reidenbach, a Smith College sophomore, appeared at the student infirmary during exam week. Rambling and delusional, she was diagnosed with mania and sent home to Ohio to recuperate. The college physician recommended further psychiatric evaluation, but Reidenbach’s parents sent her instead to their family physician. She had recovered somewhat by then, and the doctor supported her parents’ decision not to send her to a psychiatrist. Back at Smith a year later, Reidenbach suffered a second, much worse bout of psychosis. The clinicians who saw her were confronted with an incoherent, hostile and delusional woman who couldn’t keep still.

Reidenbach’s behavior was consistent with bipolar 1 disorder, which is characterized by cycling mood changes that include severe psychotic highs, and a psychiatrist diagnosed that condition. At first Reidenbach accepted treatment, but when friends and a therapist suggested she might simply have been overreacting to the stress of college life, she stopped taking medication. Only several years later, when she had another psychotic episode, did she accept that there might be something physically wrong or that both physical and psychological factors might be at work.

Even now, a quarter century after the onset of Reidenbach’s symptoms, clear answers about the underpinnings of mental illness are hard to come by. There are no diagnostic blood tests, no CAT scan that can pin down the problem. Instead, diagnoses continue to be made by artful observation. Physicians match patient behaviors with those described in the Diagnostic and Statistical Manual of Mental Disorders, or DSM—first published in 1952 and now in its fourth edition. Though many doctors consider DSM-IV to be a highly reliable tool for diagnosis and research, others say that it still requires subjective judgments. What’s more, the behavior of some patients either doesn’t fit into any DSM category or falls into the cracks among several.

Assessments of behavior and symptoms may not be the only way to diagnose mental illness, however. Working from the inside out, researchers have slowly begun to identify genetic variations that, by distorting the brain’s information-processing abilities, seem to nudge some individuals toward disease. This is still new science, and practical applications—including more precise diagnosis and better treatment—may be decades away. Yet progress in understanding the connections between a growing number of genes and conditions such as depression, bipolar 1 disorder and schizophrenia hint at what may eventually come.

Almost every one of the estimated 20,000 to 25,000 genes in every human produces at least one protein, and those proteins give rise to the activities of the cell. But small changes in the DNA sequences of genes occur regularly. While most variations are harmless, some cause disease by altering the protein or its abundance. What’s more, inherited diseases can arise from a problem with one gene (a simple example is sickle-cell anemia, a condition caused by defects in a single gene that makes the hemoglobin protein), or from interactions among a range of genetic variations as well as, frequently, environmental stresses. Scientists think mental illnesses fall into that second category. Reidenbach, for instance, is convinced her mania was triggered by stress, although scientists still can’t explain how genes and stress interact in the onset of bipolar disorder.

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Trouble Spots

Ten gene variants implicated as risk factors for two widespread mental illnesses.


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. “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.

3. “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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