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MHC fine mapping of human type 1 diabetes using the T1DGC data.

ABSTRACT: The human Major Histocompatibility Complex (MHC) is a highly polymorphic genomic region occupying approximately 4 Mb on chromosome 6p21.3. The relationship between human MHC and type 1 diabetes (T1D) has been previously investigated. To fine map the disease locus in this region, we carried out both linkage and association analyses using the Type 1 Diabetes Genetics Consortium data.Two-point linkage analysis was performed with a set of microsatellite markers assuming a fully recessive inheritance model, where we found clustering of high LOD (logarithm of the odds) scores across the MHC region. To narrow down the linkage region, we performed association analyses using both microsatellite and two sets of single nucleotide polymorphism (SNP) markers. We focused on the nuclear families containing a discordant sib-pair (an affected and unaffected sib). For the microsatellite markers, we computed the average repeat length for each individual and carried out a paired t-test.Microsatellite marker D6S2884 showed the highest association in a sharp peak with a p value of 3.15E-24. We confirmed this finding when using also SNP markers performing a McNemar's test for association. The SNPs that showed the most significant evidence of association mapped to almost the same location as the microsatellite markers.Besides the main goal of fine mapping of T1D genes, our results also illustrated the differences and the advantage of using both linkage and association analyses. After the identification of a wide peak with linkage analysis, we were able to dramatically narrow down the region by performing association analysis.

SUBMITTER: He C

PROVIDER: S-EPMC2753855 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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MHC fine mapping of human type 1 diabetes using the T1DGC data.

He C C Hamon S S Li D D Barral-Rodriguez S S Ott J J

Diabetes, obesity & metabolism 20090201

<h4>Aim</h4>The human Major Histocompatibility Complex (MHC) is a highly polymorphic genomic region occupying approximately 4 Mb on chromosome 6p21.3. The relationship between human MHC and type 1 diabetes (T1D) has been previously investigated. To fine map the disease locus in this region, we carried out both linkage and association analyses using the Type 1 Diabetes Genetics Consortium data.<h4>Methods</h4>Two-point linkage analysis was performed with a set of microsatellite markers assuming a ...[more]

PMID: 19143815

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Project description:The absence or 'missingness' of single nucleotide polymorphism (SNP) assay values because of genotype or related factors of interest may bias association and other studies. Missingness was determined for the Type 1 Diabetes Genetics Consortium (T1DGC) Major Histocompatibility Complex (MHC) data and was found to vary across the region, ranging up to 11.1% of the non-null proband SNPs, with a median of 0.3%. We consider factors related to missingness in the T1DGC data and briefly assess its possible influence on association studies.We assessed associations of missingness in the SNP assay data with human leucocyte antigen (HLA) genotype of the individual and with SNP genotypes of the parents. Within-cohort analyses were combined (over all cohorts) using (i) Mantel-Haenszel tests for two-by-two tables or (ii) by combining test statistics for larger tables and regression models. Mixed effect regression models were used to assess association of the SNP genotypes with affected status of the offspring after adjustment for parental SNP genotypes, cohort membership and HLA genotypes. Log-linear models were used to assess association of missingness in the unaffected sib assays with SNP genotypes of the probands.Missingness of SNP values near the HLA class I (A, B and C) and class II (DR, DQ and DP) loci is strongly associated with carriage of corresponding HLA genotypes within these groups. Similar associations pertain to missing values among the microsatellite data. In at least some of these cases, regions of missingness coincided with known deletion regions corresponding to the associated HLA haplotype. We conjecture that other regions of associated missingness may point to similar haplotypic deletions. Analysis of association patterns of SNP genotypes with affected status of offspring does not indicate strong informative missingness. However, association of missingness in proband data with parental SNP genotypes may impact transmission disequilibrium test (TDT)-type analyses. Comparisons of affected and unaffected siblings point to possible susceptibility regions additional to the classical HLA-DR3/4 alleles near BAT4-LY6G5B-BAT5 and NOTCH4.Potentially informative missingness in SNP assay values in the MHC region may impact on association and related analyses based on the T1DGC data. These results suggest that it would be prudent to assess the degree to which missingness may abrogate assessed SNP disease markers in such studies. Initial analyses based on comparison of affected and unaffected status in offspring suggest that at least these may be little affected.

Dataset Information

MHC fine mapping of human type 1 diabetes using the T1DGC data.

Publications

MHC fine mapping of human type 1 diabetes using the T1DGC data.

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