Identification of susceptibility genes for peritoneal, ovarian, and deep infiltrating endometriosis using a pooled sample-based genome-wide association study.
Characterizing genetic contributions to endometriosis might help to shorten the time to diagnosis, especially in the most severe forms, but represents a challenge. Previous genome-wide association studies (GWAS) made no distinction between peritoneal endometriosis (SUP), endometrioma (OMA), and deep infiltrating endometriosis (DIE). We therefore conducted a pooled sample-based GWAS and distinguished histologically confirmed endometriosis subtypes. We performed an initial discovery step on 10-individual pools (two pools per condition). After quality control filtering, a Monte-Carlo simulation was used to rank the significant SNPs according to the ratio of allele frequencies and the coefficient of variation. Then, a replication step of individual genotyping was conducted in an independent cohort of 259 cases and 288 controls. Our approach was very stringent but probably missed a lot of information due to the Monte-Carlo simulation, which likely explained why we did not replicate results from "classic" GWAS. Four variants (rs227849, rs4703908, rs2479037, and rs966674) were significantly associated with an increased risk of OMA. Rs4703908, located close to ZNF366, provided a higher risk of OMA (OR = 2.22; 95% CI: 1.26-3.92) and DIE, especially with bowel involvement (OR = 2.09; 95% CI: 1.12-3.91). ZNF366, involved in estrogen metabolism and progression of breast cancer, is a new biologically plausible candidate for endometriosis.
Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, CNRS (UMR 8104), 75014 Paris, France ; Inserm, U1016, 75014 Paris, France ; Université Paris Descartes, Sorbonne Paris Cité, Service de Gynécologie Obstétrique 2 et Médecine de la Reproduction, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, AP-HP, 74014 Paris, France.
Bruno
B
Borghese
Laboratoire Epigénétique et Environnement, Centre National de Génotypage, Institut de Génomique/CEA, 91000 Evry, France.
Jörg
J
Tost
Laboratoire Epigénétique et Environnement, Centre National de Génotypage, Institut de Génomique/CEA, 91000 Evry, France.
Magalie
M
de Surville
Laboratoire Epigénétique et Environnement, Centre National de Génotypage, Institut de Génomique/CEA, 91000 Evry, France.
Florence
F
Busato
Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, CNRS (UMR 8104), 75014 Paris, France ; Inserm, U1016, 75014 Paris, France.
Frank
F
Letourneur
Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, CNRS (UMR 8104), 75014 Paris, France ; Inserm, U1016, 75014 Paris, France.
Françoise
F
Mondon
Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, CNRS (UMR 8104), 75014 Paris, France ; Inserm, U1016, 75014 Paris, France.
Daniel
D
Vaiman
Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, CNRS (UMR 8104), 75014 Paris, France ; Inserm, U1016, 75014 Paris, France ; Université Paris Descartes, Sorbonne Paris Cité, Service de Gynécologie Obstétrique 2 et Médecine de la Reproduction, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, AP-HP, 74014 Paris, France.
Charles
C
Chapron
D002352:Carrier Proteins / Q000235:genetics; D004715:Endometriosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D010053:Ovary / Q000473:pathology; D010537:Peritoneum / Q000473:pathology; D020641:Polymorphism, Single Nucleotide
D002352:Carrier Proteins; C515832:ZNF366 protein, human