Type II diabetes remains a genetic nightmare. The major problem is identifying suitable pedigrees, sib-pairs, and populations for study. Segregation analysis data suggest that type II diabetes is likely to be polygenic, although one or more major genes could also be involved. This and the high prevalence of diabetes affect the strategies for searching for genetic mutations. Linkage analysis in classical type II diabetes pedigrees is unlikely to be successful. In addition, affected sib-pair analysis is limited because both parents are often affected, leading to bilineal inheritance. Sib-pairs with both parents alive are unusual, so identity by descent analysis is rarely feasible. Strategies to reduce bilineal inheritance by identifying sib-pairs with one known nondiabetic parent or with the second sibling having mild subclinical diabetes may be worthwhile. Identification of individuals or pedigrees with an unusual phenotype that suggests a single gene disorder, such as maturity-onset diabetes of the young, will continue to be important, for this allows linkage analysis with markers near candidate genes and exclusion mapping of chromosomal regions using highly polymorphic markers. Population association studies with candidate genes can detect mutations that have a minor role in the majority proportion of diabetic subjects, but large numbers are required and great care must be taken to exclude ethnic group differences between the diabetic and normoglycemic populations. The study of small inbred communities might be helpful because they may have fewer diabetogenic genes than outbred populations, and this would increase the power of sib-pair and population association studies. Direct screening for mutations in candidate genes (with single-strand conformation polymorphism or heteroduplex screening or with direct sequencing) in patients with the appropriate pathophysiological abnormality can be a successful strategy. The identification of well-defined diabetic pedigrees, sib-pairs, and suitable matched diabetic and nondiabetic populations will be key to the discovery of the genes for diabetes.

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