Identifying susceptibility genes using linkage and linkage disequilibrium analysis in large pedigrees.

Linkage and linkage disequilibrium tests are powerful tools for mapping complex disease genes. We investigated two approaches to identifying markers associated with disease. One method applied linkage analysis and then linkage disequilibrium tests to markers within linked regions. The other method looked for linkage disequilibrium with disease using all markers. Additionally, we investigated using Simes' test to combine p-values from linkage disequilibrium tests for nearby markers. We applied both approaches to all replicates of the Genetic Analysis Workshop 12 problem 2 isolated population data set. We reported results from the 25th replicate as if it were a real problem and assessed the power of our methods using all replicates. Using all replicates, we found that testing all markers for linkage disequilibrium with disease was more powerful than identifying markers that were in linkage with disease and then testing markers within those regions for linkage disequilibrium with the implementations that we chose. Using Simes' test to combine p-values for linkage disequilibrium tests on correlated markers seemed to be of marginal value.

Genomewide search for type 2 diabetes susceptibility genes in four American populations.

Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatments are available. Identification of biochemical or regulatory pathways involved in the disease syndrome could lead to innovative therapeutic interventions. One way to identify such pathways is the genetic analysis of families with multiple affected members where disease predisposing genes are likely to be segregating. We undertook a genomewide screen (389-395 microsatellite markers) in samples of 835 white, 591 Mexican American, 229 black, and 128 Japanese American individuals collected as part of the American Diabetes Association's GENNID study. Multipoint nonparametric linkage analyses were performed with diabetes, and diabetes or impaired glucose homeostasis (IH). Linkage to diabetes or IH was detected near markers D5S1404 (map position 77 cM, LOD = 2.80), D12S853 (map position 82 cM, LOD = 2.81) and GATA172D05 (X-chromosome map position 130 cM, LOD = 2.99) in whites, near marker D3S2432 (map position 51 cM, LOD = 3.91) in Mexican Americans, and near marker D10S1412 (map position 14 cM, LOD = 2.39) in African Americans mainly collected in phase 1 of the study. Further analyses showed evidence for interactions between the chromosome 5 locus and region on chromosome 12 containing the MODY 3 gene (map position 132 cM) and between the X-chromosome locus and region near D12S853 (map position 82 cM) in whites. Although these results were not replicated in samples collected in phase 2 of the GENNID study, the region on chromosome 12 was replicated in samples from whites described by Bektas et al. (1999).

Search for susceptibility genes, gene x gene interactions, and gene x environment interactions utilizing nonparametric linkage analysis.

There may be a different genetic basis for the two forms of the disease simulated in Problem 2 and the complex disease may be affected by environmental factors. Hence, we investigate the effects of two environmental factors. We selected 400 nuclear families from the data generated for Problem 2. Affection status was investigated in several ways. Individuals with severe and mild forms of the disease were both considered affected, individuals with only the severe form were considered affected while those with the mild form were considered unknown, and individuals with only the mild form were considered affected while those with the severe form were considered unknown. We found evidence of linkage between putative disease loci and markers in the D3G042-D3G049 and D5G031-D5G042 regions when we considered severely and mildly affected individuals as affected and also in the region D1G004-D1G013 when mildly affected individuals were considered unknown. We observed interactions between the first environmental factor and D1G043 among healthy sib pairs.