Xiaodong Jiao
National Eye Institute， National institutes of Health， USA
Purpose： The current state of understanding of genetics and positional cloning of complex and Mendelian ocular diseases will be summarized using glaucoma and Bietti crystalline corneoretinal dystrophy as examples. A brief summary of short tandem repeat (STR) and single nucleotide polymorphism (SNP) markers will be given followed by an overview of linkage analysis and association.
Method： Families with multiple individuals affected by glaucoma (POAG) were identified through the Barbados Family Study of Glaucoma (BFSG， Afro-Caribbean) . Families with multiple individuals affected by Bietti crystalline corneoretinal dystrophy (BCD) were identified by referrals from retinal and corneal specialists in the Japan， Taiwan， the United States and Switzerland (white and Asian). The inheritance of POAG was modeled using SAGE and a codominant inheritance model provided the best fit. Initial genome wide scans were carried out using the ABI md-10 marker set with a 10 cM average spacing. Fine mapping was carried out using microsatellite markers and association was measured to SNP markers in linked areas. Candidate genes were sequenced.
Result： For POAG in the Afro-Caribbean population of Barbados two main loci were identified on chromosomes 2 and 10. Association studies and candidate gene screening are continuing. BCD was localized to chromosome 4q35.1 and sequencing of candidate genes identified mutations in CYP4V2 in 23 of 25 unrelated affected individuals.Conclusion： The power of the complementary approaches of linkage and association are shown in the Barbados Family Study of Glaucoma and positional cloning of CYP4V2. These methodologies are of proven usefulness and can be applied in many other complex and Mendelian ocular diseases.
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