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From Genome Wide Association Studies to Exome Sequencing International Journal of Molecular Sciences Review Genomics of Endometriosis: From Genome Wide Association Studies to Exome Sequencing Imane Lalami, Carole Abo, Bruno Borghese, Charles Chapron and Daniel Vaiman * Institut Cochin, U1016 INSERM, UMR8104 CNRS and Université de Paris, 24 rue du Faubourg St-Jacques, 75014 Paris, France; [email protected] (I.L.); [email protected] (C.A.); [email protected] (B.B.); [email protected] (C.C.) * Correspondence: [email protected]; Tel.: +33-1-44412301; Fax: +33-1-44412302 Abstract: This review aims at better understanding the genetics of endometriosis. Endometriosis is a frequent feminine disease, affecting up to 10% of women, and characterized by pain and infertility. In the most accepted hypothesis, endometriosis is caused by the implantation of uterine tissue at ectopic abdominal places, originating from retrograde menses. Despite the obvious genetic complexity of the disease, analysis of sibs has allowed heritability estimation of endometriosis at ~50%. From 2010, large Genome Wide Association Studies (GWAS), aimed at identifying the genes and loci underlying this genetic determinism. Some of these loci were confirmed in other populations and replication studies, some new loci were also found through meta-analyses using pooled samples. For two loci on chromosomes 1 (near CCD42) and chromosome 9 (near CDKN2A), functional explanations of the SNP (Single Nucleotide Polymorphism) effects have been more thoroughly studied. While a handful of chromosome regions and genes have clearly been identified and statistically demonstrated as at-risk for the disease, only a small part of the heritability is explained (missing heritability). Some attempts of exome sequencing started to identify additional genes from families or populations, but are still Citation: Lalami, I.; Abo, C.; scarce. The solution may reside inside a combined effort: increasing the size of the GWAS designs, Borghese, B.; Chapron, C.; Vaiman, D. Genomics of Endometriosis: From better categorize the clinical forms of the disease before analyzing genome-wide polymorphisms, Genome Wide Association Studies to and generalizing exome sequencing ventures. We try here to provide a vision of what we have and Exome Sequencing. Int. J. Mol. Sci. what we should obtain to completely elucidate the genetics of this complex disease. 2021, 22, 7297. https://doi.org/ 10.3390/ijms22147297 Keywords: endometriosis; genome-wide association studies; exome sequencing; missing heritabil- ity; infertility Academic Editors: René Wenzl and Alexandra Perricos Received: 31 May 2021 1. Introduction Accepted: 29 June 2021 1.1. Epidemiology and Phenotypic Description Published: 7 July 2021 Endometriosis is a gynecologic disease affecting women of reproductive age. Its Publisher’s Note: MDPI stays neutral precise prevalence is in fact unknown, but classically estimated at around 10%. It is with regard to jurisdictional claims in characterized by two major clinical manifestations: pain and infertility. When a patient published maps and institutional affil- consults for chronic pelvic pain and infertility, endometriosis is detected in one fourth and iations. one third of the patients, respectively [1]. Pain associated with endometriosis generally increases in intensity at specific moments (during menstruations, dysmenorrhea, dyschezia, lower urinary tract symptoms and/or during intercourse, dyspareunia) or occurs continuously, albeit pain can also be absent [2]. The way infertility is connected to endometriosis is complex and differs from one Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. woman to another. First, infertility could be linked to endometrial dysfunction, leading This article is an open access article for instance to implantation failures [3]. Ovarian follicles of the endometriotic women distributed under the terms and could themselves be less able to undergo normal zygotic development. This could be conditions of the Creative Commons due to a specific accumulation of inflammatory molecules in the oocytes of endometriotic Attribution (CC BY) license (https:// women. Their number could also be reduced, especially by age, or surgery. A recent 1 creativecommons.org/licenses/by/ metabolomic study using proton nuclear magnetic resonance ( H-NMR), compared 50 pa- 4.0/). tients with Deep Infiltrating Endometriosis (DIE) versus patients with tubal obstruction Int. J. Mol. Sci. 2021, 22, 7297. https://doi.org/10.3390/ijms22147297 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 27 to a specific accumulation of inflammatory molecules in the oocytes of endometriotic Int. J. Mol. Sci. 2021, 22, 7297 women. Their number could also be reduced, especially by age, or surgery. A recent2 of 28 metabolomic study using proton nuclear magnetic resonance (1H-NMR), compared 50 pa- tients with Deep Infiltrating Endometriosis (DIE) versus patients with tubal obstruction infertilityinfertility as as control, control, and highlighted a molecular composition pointing to mitochondrial anomalies and oxidativeoxidative stressstress [4[4].]. Finally,Finally, pelvic pelvic inflammation, inflammation, caused caused by by the the presence presence of ofendometriotic endometriotic lesions, lesions, may may impair impair spermatic spermatic progression progression throughout throughout the fallopian the fallopian tubes tubesand fecundation and fecundation [3]. [3]. Histologically, endometriosis is characterized by the presence of endometrial glands and stromal tissue thatthat developdevelop asas endometrium-likeendometrium-like structures structures outside outside the the uterus. uterus. Gener- Gen- erally,ally, the the organs organs affected affected are are the the ovary ovary (endometrioma (endometrioma OMA), OMA), the the peritoneum peritoneum (superficial (superfi- cialendometriosis endometriosis SUP), SUP), the the retroperitoneum retroperitoneum and and the the anatomic anatomic structures structures located located nearnear the uterus, as for instance: uterosacral ligaments, bladder, bladder, rectum and ureters (Figure1 1).). InIn addition, the lesions can affect the myometrium and then constitute adenomyosis lesions thatthat share share many many features features with with ‘classical’ ‘classical’ endometriosis, endometriosis, and and were were once once called called endometriosisendometrio- internasis interna. Figure 1. PhenotypicPhenotypic description description of of endometriosis endometriosis and and adenomyosi adenomyosis.s. Three Three well-recognized well-recognized ph phenotypesenotypes occur occur in endo- in en- dometriosis:metriosis: superficial superficial peritoneal peritoneal lesion lesion (SUP), (SUP), ovarian ovarian endo endometriomasmetriomas (OMA) (OMA) and and deeply deeply infiltrating infiltrating endometriosis endometriosis (DIE). (DIE). In specific cases, the invasion of endometrial tissue towards the uterus leads to the establishment of adenomyosis, a spe- In specific cases, the invasion of endometrial tissue towards the uterus leads to the establishment of adenomyosis, a specific cific entity that differ from endometriosis and present different forms: diffuse adenomyosis and focal adenomyosis of the entity that differ from endometriosis and present different forms: diffuse adenomyosis and focal adenomyosis of the outer outer myometrium (FAOM). myometrium (FAOM). Three well recognized phenotypes occur: superficial peritoneal lesions (SUP), ovar- Three well recognized phenotypes occur: superficial peritoneal lesions (SUP), ovarian ianendometriomas endometriomas (OMA) (OMA) and deepand deep infiltrating infiltrating endometriosis endometriosis (DIE). (DIE). OMA areOMA cystic are masses cystic massesthat arise that from arise ectopic from ectopic endometrial endometrial tissue and tissue grow and within grow within the ovary. the DIE,ovary. is DIE, defined is de- as finedsubperitoneal as subperitoneal lesions that lesions penetrate that penetrat deepere than deeper 5 mm than under 5 mm the under peritoneal the peritoneal surface (such sur- faceas the (such uterosacral as the uterosacral ligaments) orligaments) as lesions or that as infiltratelesions that the infiltrate muscularis the propria muscularis of the propria organs ofthat the surround organs that the surround uterus (for the example uterus bladder(for example or intestine). bladder Less or intestine). frequently, Less endometriosis frequently, can occur at extragenital locations. Endometriosis is stratified by the American Society for Reproductive Medicine (ASRM) classification into four stages (I, II, III and IV) according to surgical evaluation of the size, location, severity of endometriotic lesions (superficial or Int. J. Mol. Sci. 2021, 22, 7297 3 of 28 deep) and the extension of adhesions [5,6]. Evidence suggests that endometriosis is a stable disease (as opposed to a proliferative disease such as cancer) that progresses to fibrosis over time [7–10]. 1.2. Diagnosis Endometriosis is difficult to diagnose for several reasons [11]. One of the factors is probably a lack of understanding of the disease by health-care professionals. Furthermore, uncertainty exists regarding the pathogenesis of endometriosis. The heterogeneity of the disease, with three endometriosis phenotypes, and the possibility of asymptomatic dis- ease as well as the potential comorbid presence of adenomyosis can complicate diagnosis. History-taking by patient interviews is essential for diagnosing endometriosis [11]. Pelvic pain is the cardinal symptom
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