Yale researchers are going to the ends of the earth to find the genetic causes of human disease. The inspiration for their globetrotting comes from the work of Richard Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics, who has pioneered the discovery of human disease genes by studying “outliers,” people and families with extreme forms of common diseases.

Lifton’s technique depends on finding rare families who show severe forms of inherited conditions like high blood pressure, heart attack or stroke. The far-flung families, who might live in Turkey or Tehran, Brazil or the South Pacific, present a worst-case scenario of genetic mutations that, in milder forms, contribute to the far more common types of the same killers. Each time a gene is uncovered in one of these families, it sheds light on the pathways that underlie related but more widespread diseases, and presents potential new targets for therapies. Using this approach, Lifton and colleagues have identified 10 genes that cause very high blood pressure and 10 that cause low blood pressure.

In the past, Lifton says, human genetics occupied itself with truly rare diseases, like hemophilia or inborn errors of metabolism, but that has changed. “With the tools of the human genome project,” he says, “we can now begin to figure out the inherited susceptibilities to virtually every common disease that afflicts mankind.”

In a recent example, cardiologist Arya Mani, M.D., assistant professor of medicine, identified a family in Iran with early severe coronary artery disease. The affected members had heart attacks before age 50, and, with Lifton’s help, Mani showed that their disease traced back to a single genetic mutation. What’s more, this single defect caused diabetes, high blood pressure, and high levels of “bad” LDL cholesterol and fats in the blood. This constellation of risk factors for heart disease is termed metabolic syndrome and occurs together in many Americans. The pathway Mani uncovered, which affects all of these risk factors, presents opportunities for developing new medicines to treat metabolic syndrome and prevent heart disease.

Another Lifton trainee, Murat Gunel, M.D., associate professor of neurosurgery and neurobiology and chief of neurovascular surgery, has forged a link between Yale and his native Turkey to study families with a predisposition to stroke.

Other researchers around Yale have taken Lifton’s lead and looked at rare cases to learn about more general causes of disease. In 2005, Matthew W. State, M.D., Ph.D., Harris Associate Professor of Child Psychiatry, identified the first gene whose mutation causes Tourette’s syndrome, a common development disorder in children. His discovery and concurrent findings from Jeffrey R. Gruen, M.D., associate professor of pediatrics, of a gene involved in the learning disability dyslexia were both cited in a list of the top 10 scientific breakthroughs of 2005 by the leading journal Science.

An alternative approach to unlocking the genetic secrets of common diseases is also flourishing at Yale. In contrast to rare mutations with dramatic effects, there are numerous common variations in many genes that have relatively small effects on disease on their own, but collectively can add up to a big risk for conditions like heart disease, autism or Alzheimer’s disease.

Finding these small effects requires collecting a large number of patients and an equally large number of matched control subjects without the disease. Then, researchers must scan half a million spots on the DNA of each person to find the differences in their genetic codes. After that, sophisticated mathematical models determine if there is an association between particular genetic differences and disease.

Two of the earliest successes of this whole-genome association approach took place at Yale. In 2005, a group led by Josephine J. Hoh, Ph.D., associate professor of epidemiology and of ophthalmology and visual sciences, identified common variants in an immune protein associated with age-related macular degeneration (AMD), the leading cause of blindness among the elderly. In 2006, Hoh joined with collaborators in Hong Kong, comparing Chinese and Caucasian populations with AMD to zero in on a gene involved in the most serious, “wet” form of the disease. Also in 2006, Judy H. Cho, M.D., associate professor of medicine and genetics, uncovered the involvement of another immune signaling molecule, the interleukin-23 receptor, in Crohn’s disease, an autoimmune inflammation of the intestinal tract.

A third and extremely active avenue of human genetic research at Yale does not even involve humans, at least not directly. The time-honored staples of basic genetic research—that is, simple model organisms including mice, fruit flies, fish and worms—are increasingly being drafted to study human disease mechanisms. “A lot of biology is conserved from these simple organisms all the way up to humans,” explains Professor of Genetics Tian Xu, Ph.D. “So, when we identify mutations in these simple systems, they are proving to be directly applicable to humans.”

By finding cancer-causing mutations in fruit flies, Xu’s research formed the basis for an experimental drug now in human testing. Recently, Xu developed a novel method for rapidly producing large numbers of mice with single-gene mutations, and he is working with neuropsychiatrist State to identify mutants with interesting behavioral symptoms. The researchers will then examine those genes in State’s collection of 1,000 families with various neurological conditions. “This will dramatically speed up the process of discovering disease genes in humans,” Xu says.

Even Xu’s mice are international travelers. Much of the breeding work for his project is being done in China, but the mice will soon be shipped to Yale’s new West Campus in West Haven, Conn., where they will be tested for disease-related traits in one of the first projects to make a new home in that new facility.

MEDICINE tomorrow

Yale School of Medicine is known worldwide for its cutting-edge research on the genetic bases of human disease. You can help to realize the promise of new treatments, the development of personalized medicine and breakthroughs that will lead to the prevention of disease by supporting our researchers and clinicians. The gift opportunities listed below can fund important work in genetics or in any other area of donor interest.

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For more information about gift opportunities, visit Yale Tomorrow Medicine or contact Jancy Houck, Associate Vice President for Development and Director of Medical Development at (203) 436-8560.