Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26

Abstract

Endometriosis is a common gynecological disease that affects up to 10% of women in their reproductive years. It causes pelvic pain, severe dysmenorrhea, and subfertility. The disease is defined as the presence of tissue resembling endometrium in sites outside the uterus. Its cause remains uncertain despite >50 years of hypothesis-driven research, and thus the therapeutic options are limited. Disease predisposition is inherited as a complex genetic trait, which provides an alternative route to understanding the disease. We seek to identify susceptibility loci, using a positional-cloning approach that starts with linkage analysis to identify genomic regions likely to harbor these genes. We conducted a linkage study of 1,176 families (931 from an Australian group and 245 from a U.K. group), each with at least two members--mainly affected sister pairs--with surgically diagnosed disease. We have identified a region of significant linkage on chromosome 10q26 (maximum LOD score [MLS] of 3.09; genomewide P = .047) and another region of suggestive linkage on chromosome 20p13 (MLS = 2.09). Minor peaks (with MLS > 1.0) were found on chromosomes 2, 6, 7, 8, 12, 14, 15, and 17. This is the first report of linkage to a major locus for endometriosis. The findings will facilitate discovery of novel positional genetic variants that influence the risk of developing this debilitating disease. Greater understanding of the aberrant cellular and molecular mechanisms involved in the etiology and pathophysiology of endometriosis should lead to better diagnostic methods and targeted treatments.

Figure 1

Linkage (MLS) curves for all chromosomes in the combined data set, prior to inclusion of additional fine markers. This composite figure shows relative chromosome lengths. The genetic map of each chromosome is shown on the X-axis, and the MLS is shown on the Y-axis. Thresholds for significant (MLS=3.08) and suggestive (MLS=1.88) genomewide linkage are indicated by horizontal lines.

Figure 2

Fine mapping of chromosome 10 peak (A) and chromosome 20 peak (B). Linkage (MLS) curves are presented for the chromosomes before and after the addition of several markers, shown in different colors. Microsatellite markers are shown in genetic map order along the X-axis, with positions given in cM (Haldane). The Y-axis represents the MLS.

Figure 3

Study of origin strata at chromosome 10 peak (A) and chromosome 20 peak (B). Linkage (MLS) curves that include the fine markers are presented for the Australian and U.K. studies separately and also for the combined data set. Microsatellite markers are shown in genetic map order along the X-axis, with positions given in cM (Haldane). The Y-axis represents the MLS. A, Results show the increase in MLS when the two data sets are combined.

Figure 4

Linkage in chromosome 10 conditional on linkage to chromosome 20. Chromosome 10 linkage curves are presented for families showing linkage at the chromosome 20 peak. Curves show MLS results for families linked to the chromosome 20 peak in the two studies separately and for all linked families. Microsatellite markers are shown in genetic map order along the X-axis, with positions given in cM (Haldane). The Y-axis represents the MLS.