TABLE 2

Test for replication of stratified loci in T1DGC set 3 families

StratificationcMLODPCorrected LOD*LOD-1 intervalP in set 3GWAS SNP
HLA IBD
 Chromosome
  19q1359.02.830.00021.7554.0–64.50.006PRKD2
HLA MIS
 Chromosome
  19p23.03.040.000091.9818.0–27.5NS
HLA DR3/4
 Chromosome
  16q2399.13.180.000062.1096.0–110.00.06CTRB2
INS
 Chromosomes
  6q1387.03.340.000042.2681.5–900.004
  8q1383.54.190.000013.1180.0–88.0NS§
Male subjects90.02.900.000131.5986.5–91.50.0002
 Chromosomes
  6q14
  6q21116.03.100.000082.02109.0–118.50.03
  6q22127.03.760.000022.68120.0–130.00.09CENPW
  11p152.53.180.000072.100–7.0NSINS
  19p139.53.220.000062.145.0–13.5NSC19orf19
AAD
 Chromosomes
  7q36172.53.130.000092.05163.5–179.5NS§
  • Loci showing LOD scores >3 from the stratified analyses and those showing significant differences between stratified sets (Fig. 4) were tested in the third collection of T1DGC families. Pedigree files of the relevant chromosomes from the third T1DGC cohort were stratified according to criteria presented above, and P values were calculated by Merlin. Genome-wide association scan SNPs that showed significant association with type 1 diabetes in or near to these regions are shown as candidates for these loci. NS, not significant; P > 0.1.

  • *Final corrected LODs were obtained by subtracting 1.08, the log of the number of stratification tests (n = 12) (32).

  • †Note that INS stratification shows that the 6q13 score shows a signal from siblings who each have at least one protective T allele, whereas the 8q13 signal comes from those homozygous AA (i.e., the INS risk allele). We interpret this as suggesting that the chromosome 6q locus is able to overcome the protective affect of the INS T allele. In contrast, the 8q13 locus may interact with the INS susceptibility alleles to increase disease risk.

  • ‡LOD scores for chromosome 6q loci were adjusted for residual HLA linkage by subtracting ELOD (see text).

  • §Markers outside the LOD-1 interval gave P values of 0.003 and 0.01, respectively, in appropriately stratified set 3 families.