To date, several susceptibility loci for systemic lupus erythematosus (SLE) have been identified by individual genome-wide scans, but many of these loci have shown inconsistent results across studies. Additionally, many individual studies are at the lower limit of acceptable power recommended for declaring significant linkage. The genome search meta-analysis (GSMA) has been proposed as a valid and robust method for combining several genome scan results. The aim of this study is to investigate whether there is any consistent evidence of linkage across multiple studies, and to identify novel SLE susceptibility loci by using GSMA method. Twelve genome scan results generated from nine independent studies have been used for the present GSMA. All together, the data consists of 605 families with 1,355 SLE affected individuals from three self-reported ethnicities; Caucasian, African-American, and Hispanic. For each study, the genome was divided into 120 bins (30 cM) and ranked according to the maximum evidence of linkage within each bin. The ranks were summed and averaged across studies following which the significance was assessed by the permutation tests. The present study identified two genomic locations at 6p22.3-6p21.1 and 16p12.3-16q12.2 that met genome-wide significance (p<0.000417). The identified region at 6p22.3-6p21.1 contains the HLA region. The combined p-values using Fisher's method also supported the significance in these regions. Clustering of significant adjacent bins was observed for chromosomes 6 and 16. Additionally, there are 12 other bins with two point-wise p-values (Psumrnk and Pord) <0.05, suggesting that these bin regions are highly likely to contain SLE susceptibility loci. Among them, present GSMA also identified two novel regions at 4q32.1-4q34.3 and 13q13.2-13q22.2. However, separate analysis using only Caucasian populations identified the strongest evidence for linkage at chromosome 6p21.1-6q15 (Psumrnk=0.00021). One interesting novel region suggests that 3q22.1-3q25.33 (Psumrnk=0.01376) may be an ethnicity-specific SLE linkage. In summary, the present GSMA have identified two statistically significant genomic regions that reconfirmed the SLE linkage at chromosomes 6 and 16.
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Acknowledgments The authors gratefully acknowledge Dr. Cathryn Lewis, for her helpful comments and discussion. The authors also thank Ms. Summer Frank and Xana Kim for proofreading. This work was supported by the National Institutes of Health grants (AR048928, AI063622, RR020143, and AR049084).
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