Education

• 1967 A.B. Harvard College
• 1971 Ph.D. University of Michigan (Human Genetics)

Research Interests

The research in this lab concerns the genetics of susceptibility to multifactorial or "complex"
 human diseases, in particular the genetics of diabetes. Susceptibility to these diseases is
 probably the result of allelic variation at several (or many) genes. Diabetes is a common
 disease, especially among adults, and constitutes a major health problem: in a substantial
 fraction of patients, the medical complications of diabetes eventually lead to blindness, kidney
 failure, or amputations. There is clearly more than one type of diabetes and different genes are
 involved in the different types; there is likely a genetic contribution to development of
 complications as well. For both diabetes and another complex endocrine disease, polycystic
 ovary syndrome (PCOS), our long-term aim is to identify all the relevant genes by genetic
 linkage studies and to characterize the genes at the molecular level. 

 Type 1 diabetes (Insulin-Dependent Diabetes Mellitus)
 Most of our work has been on the best-studied example of such a complex human disease,
 type 1 (juvenile-onset type) diabetes. We have carried out a "genome screen" for genes
 that influence susceptibility, and found a previously unknown region of chromosome 1 that
 shows evidence for linkage to type 1 diabetes (Concannon et al., 1998). With a combination
 of linkage studies and physical mapping, we are narrowing the chromosomal region and using
 the techniques of positional cloning to find the relevant gene.

 PCOS - Candidate Genes
 For some complex diseases, a genome screen is impractical and instead we test individual
 genes. Candidate genes are selected on the basis of known functional relationship to the
 disease or trait. We test these in a large number of patients or families, usually by looking for
 genetic linkage with some nearby gene or "genetic marker." We have used this approach
 (Urbanek et al., 1999) to test candidate genes for "polycystic ovary syndrome" (PCOS),
 which affects approximately 5% of women, and results in infertility, obesity, and diabetes. The
 candidate gene approach is also being used to test for genetic susceptibility to diabetic kidney
 disease, which accounts for one-third of severe kidney disease in the U.S. The very large,
 and growing, catalogues of known human genes make this an effective method for finding
 the genes that contribute to complex diseases.

 Statistical Genetics
 Genetic studies of complex diseases have a statistical aspect, and we have developed several
 new statistical techniques and tests for this purpose (Spielman and Ewens, 1996). This work
 is integrated with the laboratory studies for a comprehensive approach to complex diseases.

 References

      Spielman RS, Ewens WJ: The TDT and other family-based tests for linkage
      disequilibrium and association. Am J Hum Genet 59:983-989, 1996.

      Cheung VG, Gregg JP, Gogolin-Ewens KJ, Bandong J, Stanley CA, Baker L, Higgins
      MJ, Nowak NJ, Shows TB, Ewens WJ, Nelson SF, Spielman RS: Linkage
      disequilibrium mapping without genotyping. Nature Genet 18:225-230, 1998.

      Concannon P, Gogolin-Ewens KJ, Hinds DA, Wapelhorst, Morrison VA, Stirling B,
      Mitra M, Farmer J, Williams SR, Cox NJ, Bell GI, Risch N, Spielman RS: A
      second-generation screen of the human genome for susceptibility to type 1
      (insulin-dependent) diabetes mellitus (IDDM). Nature Genet 19:292-296, 1998.

      Urbanek M, Legro RS, Driscoll DA, Azziz R, Ehrmann DA, Norman RJ, Strauss JF
      III, Spielman RS, Dunaif A: Thirty-seven candidate genes for polycystic ovary
      syndrome: Strongest evidence for linkage is with follistatin. Proc Nat Acad Sci USA
      96: 8573-8578, 1999.