Overview

Large-scale replication study to identify susceptibility loci for systemic lupus erythematosus (SLE). A custom SNP array (Illumina Infinium II) consisting of 12,864 variants selected from 2,466 regions that showed nominal evidence of association to SLE was designed. Two independent SLE case and control populations from the United States (1,129 SLE cases and 2,991 controls) and Sweden (834 SLE cases and 1,338 controls) were genotyped. Further evidence of association with SLE for 21 of the variants was obtained, including 9 loci that reached genome-wide significance in the combined dataset. To identify previously unknown SLE risk loci, 3,188 SNPs from 2,446 distinct loci that showed evidence of association to SLE were examined in the genome-wide dataset - which comprised 502,033 SNPs genotyped in 1,310 SLE cases and an expanded set of 7,859 controls. Using this dataset, IMPUTE version 1 was used to infer genotypes using HapMap Phase II CEU samples as a reference. This identified five new SLE risk loci with a combined P value that exceeded the genome-wide threshold for significance.

Study Type
Whole Genome Association Study
Samples
GroupPhenotypePopulationCasesControlsFamiliesTrios
DiscoverySLE13107859--
ReplicationALZ-2215--
ReplicationSLE19632114--
Exclusion Criteria

US data. 1,464 cases and 3,078 controls were genotyped on the custom 12K chip. 116 individuals were excluded who had >5% missing data and 279 individuals based on cryptic relatedness and duplicate samples based on identity-by-state status (PI_Hat > 0.15). Only SNPs with <5% missing data, Hardy-Weinberg equilibrium P value > 1 times 10-6, minor allele frequency > 0.01% and P > 1 times 10-5 in a test for differential missingness between cases and controls were included. After applying the above filters, 1,144 cases and 3,003 controls and 11,024 SNPs were available for analysis.

Swedish data. A set of 888 cases and 527 controls genotyped on the custom 12K chip was available for analysis. A separate set of 1,115 Swedish controls genotyped on the 317K Illumina chip was also incorporated into the analysis. The following steps were used to combine the two datasets: (i) an overlapping set of 6,789 SNPs between the 12K and 317K data was created to examine the Swedish replication cohort for cryptic relatedness and duplicate samples. As a result, 313 samples were excluded (PI_Hat > 0.15). After quality control checks, 863 cases and 523 controls were genotyped on the custom 12K chip and 831 controls genotyped on the 317K chip, (ii) the 831 Swedish controls genotyped with the 317K array were imputed to create a final set of 11,394 overlapping SNPs. The SNPs in this dataset were filtered using the same thresholds as described above.

Study Association

RegionLocationGene(s)MarkerAlleleMAFP ValueOdds Ratio
1p13.2chr1:113296527-114009223PTPN22  rs2476601G > A0.1003.40e-12C1.35 (1.24-1.47)C
1q23.3chr1:161419627-161668253FCGR2A  rs1801274A > G0.5004.10e-04C1.16 (1.09-1.20)C
1q25.1chr1:173128850-173329925TNFSF4  rs2205960G > T0.2306.30e-09C1.22 (1.15-1.30)C
1q25.3chr1:183207701-183585146NMNAT2  rs2022013T > C0.4001.50e-03C1.09 (1.03-1.16)C
1q32.1chr1:206709013-206867232IL10  rs3024505G > A0.1604.00e-08C1.19 (1.11-1.28)C
2q32.3chr2:190995776-191143008STAT4  rs7574865G > T0.2301.40e-41C1.57 (1.49-1.69)C
3p14.3chr3:58170962-58559081PXK  rs2176082G > A0.2801.20e-05C1.17 (1.10-1.25)C
4q24chr4:101780701-102173465BANK1  rs10516487G > A0.3008.30e-04C1.11 (1.04-1.18)C
5q33.1chr5:151012930-151104264TNIP1  rs7708392G > C0.2403.80e-13C1.27 (1.10-1.35)C
5q33.3chr5:160415666-160540930PTTG1  rs2431099A > G0.4801.60e-06C1.15 (1.09-1.22)C
6p21.31chr6:34539227-35395980UHRF1BP1  rs11755393A > G0.3502.20e-08C1.17 (1.10-1.24)C
6q21chr6:106150492-106380042ATG5  rs2245214C > G0.3701.20e-05C1.15 (1.09-1.21)C
6q21chr6:106100256-106180825PRDM1  rs6568431C > A0.3807.10e-10C1.20 (1.14-1.27)C
6q23.3chr6:137707015-137953948TNFAIP3  rs5029937G > T0.0305.30e-13C1.71 (1.51-1.95)C
6q23.3chr6:137568592-137806067TNFAIP3  rs6920220G > A0.2104.00e-07C1.17 (1.10-1.25)C
7p15.1chr7:28080094-28222707JAZF1  rs849142C > T0.4901.50e-09C1.19 (1.13-1.26)C
7p21.3chr7:8128836-8175578ICA1  rs10156091C > T0.1006.50e-04C1.16 (1.06-1.27)C
7q32.1chr7:128911686-129137466IRF5  rs2070197T > C0.1105.80e-24C1.88 (1.78-1.95)C
8p23.1chr8:11426026-11546260BLK  rs2736340C > T0.2507.90e-17C1.35 (1.27-1.43)C
11p15.5chr11:413012-721570PHRF1  rs4963128C > T0.3304.90e-09C1.2 (1.14-1.27)C
16p11.2chr16:30884392-31373327ITGAM  rs11860650C > T0.1301.90e-20C1.43 (1.32-1.54)C
19p13.2chr19:10284572-10517872TYK2  rs280519G > A0.4807.40e-05C1.13 (1.06-1.21)C
22q11.21chr22:21454896-21649639UBE2L3  rs5754217G > T0.1902.30e-06C1.20 (1.13-1.27)C
MHCchr6:32350867-32661068HLA-DRB1  rs3135394A > G0.1002.00e-60C1.98 (1.84-2.14)C
MHCchr6:32408969-32714358HLA-DRB1  rs9271366A > G0.1601.40e-07C1.26 (1.18-1.36)C
Xq28chrX:153797346-154117459MECP2  IRAK1  rs2269368C > T0.1407.50e-07C1.11 (1.01-1.22)C

Criteria

GDXHsS00015 meets the following criteria:

Criteria Name
Details
Disease Tags
Study for a Disease 

Publications

PMIDTitleFirst AuthorJournalDisease(s)Date