The identification of a specific X-linked polymorphism for schizophrenia in Caucasian Americans may allow investigators to make progress in understanding the broader genetic bases of the disease, according to an article published online February 11th by the American Journal of Medical Genetics.

The polymorphism on the X chromosome is called HOPA12pb, and it is carried by roughly 2 percent of Caucasian Americans, most of whom do not show signs of schizophrenia. Based on genetic analysis, the polymorphism, which probably occurred as a single mutation in a common ancestor about 100,000 years ago, is associated with overall benefits for human survival.

"While this polymorphism makes us more vulnerable to a certain illness, in this case schizophrenia, overall it is evolutionarily beneficial," said Robert Philibert, MD, PhD, the study's principal investigator. "Traditionally, genes that are selected for human evolution affect two things -- resistance to infection and infant survival. This gene may be involved in both of these positive features."

Although nearly 1 in 50 people of European extraction has the HOPA polymorphism, only a small minority of these people actually have schizophrenia. About 1 in 30 men with the polymorphism has the condition. Men are more likely than women to have clinical schizophrenia because the gene is located on the X chromosome.

People with HOPA-linked schizophrenia may have hallucinations. However, they do not have other symptoms found with most other forms of schizophrenia such as compromised thinking, decreased attention, and loss of emotion.

"We knew the gene causes a specific form of schizophrenia, but we didn't know that the type was associated with a good prognosis and marked by absence of negative symptoms," Philibert said. "Most individuals with this positive symptom schizophrenia are able to function in society and hold down jobs."

He added that the gene cannot by itself cause schizophrenia but must interact with other genes and environmental factors to result in illness. In addition to sometimes leading to schizophrenia, it also can cause hypothyroidism or obesity. "It is critical to understand those interactions. If we can modulate them, we may be able to block the ill effects of this gene and keep the beneficial aspects," Philibert said.

"There are at least 25 genes in the gene complex in which HOPA participates. Several of the genes are known to be involved with other forms of human illness. Because this polymorphism is relatively common and because we have human models of it, it can be used as a paradigm to understand those other gene defects," Philibert added.

The type of evolutionary advantage -- resistance to disease -- that the UI team saw in the HOPA polymorphism also can be seen in a polymorphism linked to sickle cell anemia. In that condition, one copy of the polymorphism causes mild cell abnormalities but also provides resistance to malaria and thus promotes human survival. However, two copies of the variant gene cause the debilitating disease sickle cell anemia.