Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs

Abstract

Crohn's disease and ulcerative colitis (the inflammatory bowel diseases) have a strong genetic component. Although over 20 putative susceptibility loci have been identified by individual genome scans, the majority of these loci have not been replicated. Many individual studies are at the lower limit of acceptable power for complex disease linkage analysis. Genome scan meta-analysis (GSMA), by use of sample sizes an order of magnitude greater than individual linkage studies, has increased power to detect novel loci, may confirm or refute regions detected in smaller individual studies, and enables regions to be prioritized for further gene identification efforts. Genome scan data (markers, significance scores) were obtained from 10 separate studies and meta-analysis was performed using the GSMA method. These studies comprised 1952 inflammatory bowel disease, 1068 Crohn's disease and 457 ulcerative colitis affected relative pairs. Study results were divided into 34 cM chromosomal bins, ranked, weighted by study size, summed across studies and bin-by-bin significance obtained by simulation. A region on chromosome 6p (containing the HLA) met genome wide significance for inflammatory bowel disease. Loci meeting suggestive significance for inflammatory bowel disease were 2q, 3q, 5q, 7q and 16 (NOD2/CARD15 region); Crohn's disease, 2q, 3q, 6p, 16 (NOD2/CARD15 region), 17q, 19p; and ulcerative colitis, 2q. Clustering of adjacent bins was observed for chromosomes 6p, 16, 19p. The meta-analysis has identified novel loci and prioritized genomic regions for further gene identification studies.

Meta-analysis of genome-wide linkage studies for multiple sclerosis, using an extended GSMA method

“…In other GSMA studies of autoimmune diseases, linkage to HLA affected only bins 6_1 to 6_3, and bin 6_4 was not significant. 5,6,23 This result may therefore indicate a novel susceptibility locus for MS on chromosome 6q. Nominal evidence for linkage on chromosome 10 is seen in the full meta-analysis (weighted and unweighted) and when the IMSGC study is included (suggestive linkage), with the most significant results obtained in bins 10_3 and 10_4 (approximate cytogenetic bands 10p12.1 -q23.33).…”

Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility

“…1 UC is a complex polygenic condition, characterized by an inappropriate mucosal immune response within the gut to the commensal bacterial flora, leading to ulceration of the colonic mucosa. 2 Genome-wide screening in UC has demonstrated replicated linkage to several chromosomal regions, including regions on chromosomes 12 3,4 and 19 5,6 termed IBD2 and IBD6, respectively. Within the IBD2 loci lies the lectin-like natural killer (NK) receptor gene NKG2D (KLRK1) located at 12p13.2-p12.3.…”

Identification of chromosomal regions linked to premature myocardial infarction: a meta-analysis of whole-genome searches

“…GSMA is one of the best-established methods for meta-analysis of such data (Zintzaras and Ioannidis 2005a;Levinson et al 2003;Wise et al 1999). GSMA has already been applied to genome scans of several diseases (Zintzaras and Ioannidis 2005a, b;Ioannidis et al 2006;Trikalinos et al 2006;van Heel et al 2004). Zintzaras and Ioannidis (2005a, b) developed an extension of the GSMA by evaluating heterogeneity between different genome scans in the context of GSMA (called HEGESMA: heterogeneity based genome scan meta-analysis).…”