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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
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Laboratory of Statistical Genetics, The Rockefeller University, New York, NY, USA. che@mail.rockefeller.edu
Hamon
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Li
D
D
Barral-Rodriguez
S
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Ott
J
J
D000071797:Butyrophilins; D002874:Chromosome Mapping; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics
C408263:BTNL2 protein, human; D000071797:Butyrophilins; D008562:Membrane Glycoproteins; C106075:NOTCH4 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch; C092008:PRRC2A protein, human