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The study used genome-wide enrichment analysis to examine overlap in common genetic variants between endometriosis and obesity-related traits, leveraging GWAS data and an independent meta-GWAS in European ancestry individuals. The authors found a genome-wide significant intergenic locus on 7p15.2 associated with both endometriosis and fat distribution (WHRadjBMI), and they observed significant enrichment of shared variants between endometriosis and fat distribution that was stronger in more severe (Stage B) cases, while finding no enrichment between endometriosis and BMI (P = 0.79). Beyond 7p15.2, they identified four additional loci (in/near KIFAP3, CAB39L, WNT4, GRB14) with evidence of involvement in both endometriosis and WHRadjBMI, noting that KIFAP3 and CAB39L were novel for both traits, and they reported pathway overrepresentation of developmental processes/WNT signalling (P = 6.41 × 10(-4)). This paper is centrally about endometriosis — it identifies genetic loci and enriched shared architecture between endometriosis and fat distribution traits.
Abstract
Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 x 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 x 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 x 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.
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Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci
Date Issued
2015-01-01
Author(s)
Rahmioglu, Nilufer
Macgregor, Stuart
Drong, Alexander W.
Hedman, Åsa K.
Harris, Holly R.
Randall, Joshua C.
Prokopenko, Inga
International Endogene Consortium,
The Giant Consortium,
Nyholt, Dale R.
Morris, Andrew P.
Montgomery, Grant W.
Missmer, Stacey A.
Lindgren, Cecilia M.
Zondervan, Krina T.
DOI
10.1093/hmg/ddu516
Abstract
Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.
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