Is Mental Illness Inherited?

By Claudia Wallis

It is rare to find a chatterbox among the Amish of Lancaster County, Pa. Rarer still is a flamboyant personality, a braggart, a show-off or, at the other extreme, someone who is deeply depressed or suicidal. In this community of quiet-spoken, humble pacifists, such behavior "really stands out against the social landscape," observes Medical Sociologist Janice Egeland, who has spent more than 25 years among the Old Order Amish, as the group is formally known. When it does occur, the Amish often have an explanation: "Siss im blut," they say; the peculiar behavior is "in the blood."

Last week Egeland, who is from the University of Miami School of Medicine, and a group of scientists at Yale and M.I.T. confirmed that traditional Amish explanation. By employing the tools of molecular biology along with the handwritten genealogical records of Amish families, they showed that the mental disorder known as manic depression is indeed at least partly a matter of bloodlines. Their report, published in the journal Nature, conclusively linked cases of manic depression in an Amish family to genes in a specific region of human chromosome 11. "This is the first demonstration of a possible genetic basis for one of the major mental disorders," says Dr. Darrel Regier, director of the division of clinical research at the National Institute of Mental Health (NIMH). "The study ushers in a new era of psychiatric research."

Usually beginning somewhere between the ages of 15 and 35, manic depression afflicts about 1 in every 100 people. Because it causes its victims to oscillate between two extreme emotional states, it is also known to psychiatrists as bipolar affective disorder. In the manic phase, victims become expansive and extravagant, are often unable to sleep or eat, and may talk incessantly. Some assume airs of grandeur. The depressive phase plunges them into hopelessness, loneliness and boundless guilt, feelings that sometimes lead to suicide.

Researchers have long suspected that heredity plays a role in some if not all cases, and the Amish present an ideal setting in which to test that hypothesis. Not only does bipolar behavior contrast sharply with the community's quiet ways, making it easy to diagnose, but a number of confounding factors that might contribute to such behavior are absent: alcoholism, drug abuse, unemployment, divorce and violence are extremely rare. In addition, the Amish have large families (seven children on average) and keep genealogical records worthy of Mendel. Best of all, they represent a closed genetic pool. All 12,500 Amish in Lancaster County are descended from 20 or 30 couples who emigrated from Europe in the early 1700s, and only a handful of outsiders have ever married in.

Though manic depression is no more common among the Amish than other groups, Egeland's research turned up 32 active cases. All proved to have family histories of the disease going back several generations. Curiously, all of the 26 suicides documented in the community since 1880 occurred in just four of these families.

The study published last week focused on one 81-member clan. Fourteen members had been diagnosed with manic depression and another five with other mental disorders. Thanks to unusual cooperation from the family, the researchers were able to obtain blood from each member and then isolate DNA from each sample. Using so-called restriction enzymes, they "cut" the DNA into segments. When they compared gene segments from manic depressives with those from normal family members, they found a discrepancy in a region of chromosome 11. Their conclusion: a gene or group of genes in or near this region confers a predisposition to manic depression.

The researchers also confirmed that children of individuals with this genetic anomaly have a 50% chance of inheriting it. However, only 63% of those carrying the gene show signs of the disorder, which suggests that other factors -- perhaps environmental -- also play a role in bringing on the disease.

Does the same genetic defect play a role in all manic depression? Not necessarily. Two studies also published in last week's Nature revealed no link between the chromosome 11 site and manic depression in six non-Amish families prone to the disease. Still, these findings do not undermine the important discovery of a genetic basis for the ailment. Instead, observes NIMH Psychiatrist Sevilla Detera-Wadleigh, who led one of the other studies, they suggest that more than one gene may be involved in manic depression.

The next step for scientists will be to identify the particular gene or genes responsible for manic depression. This will enable them to understand the biochemical basis for the disease, which could lead to better treatments. (The drug lithium carbonate is effective in 70% to 75% of cases.) It could also lead to tests for the diagnosis and identification of people at risk for bipolar disorder.

Egeland hopes for a more immediate benefit from her work. "Too often," she says, "personal embarrassment and social stigma are associated with an illness whose cause is beyond the control of the individual." That stigma should be lessened and more people should be encouraged to seek treatment now that scientists have confirmed the source of manic depression can indeed be im blut.

With reporting by Andrea Dorfman/New York and Dick Thompson/Washington