This is a Mentored Research Scientist Development Award proposal. The purpose of this application is to acquire a broad background in psychiatric and molecular genetics, and in particular the methods and models of human quantitative genetics, necessary to the long-term career goal of becoming an independent investigator specializing in the application of the statistical techniques of survival analysis to genetic modeling of the complex psychiatric disorders. There are now nine neurological disorders which have been confirmed to be caused by expanding triplet-repeat polymorphisms, and findings suggestive of such a mechanism have been reported for schizophrenia and bipolar disorder. Age-of-onset anticipation, wherein children tend to develop disease at earlier ages than their affected parents, is the primary evidence in favor of a triplet-repeat mechanism prior to the actual cloning of a disease gene. Establishing such an underlying mechanism can have profound implications for gene mapping protocols, as well as for clinical treatment and genetic counseling. However, proper statistical methods for the detection of age-of-onset anticipation remain to be developed and will need to draw on the mathematical field of survival analysis. The candidate, a theoretical statistician with extensive expertise in survival analysis, proposes to acquire this additional training in order to address the class of problems arising in human genetics in connection with triplet-repeat mechanisms, and especially, for those psychiatric disorders for which triplet-repeats have been implicated: schizophrenia and bipolar disorder. Training will be provided through course work at the University of Iowa; a formal tutorial; work in a molecular genetics laboratory; training in field methods in psychiatric epidemiology at Columbia University: and ongoing consultation with a panel of distinguished psychiatrists. The University of Iowa has an outstanding research program in psychiatric and statistical genetics. Initial research will concentrate on new statistical tests for age-of-onset anticipation. Subsequently more general segregation and linkage models incorporating age-of-onset distributions for complex disorders will be developed.
| Huang, Jian; Jiang, Yanming (2003) Genetic linkage analysis of a dichotomous trait incorporating a tightly linked quantitative trait in affected sib pairs. Am J Hum Genet 72:949-60 |
| Vieland, Veronica J; Huang, Jian (2003) Two-locus heterogeneity cannot be distinguished from two-locus epistasis on the basis of affected-sib-pair data. Am J Hum Genet 73:223-32 |
