Dataset Information

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

ABSTRACT: Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

SUBMITTER: Rahmioglu N

PROVIDER: S-EPMC10042257 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

Rahmioglu Nilufer N Mortlock Sally S Ghiasi Marzieh M Møller Peter L PL Stefansdottir Lilja L Galarneau Geneviève G Turman Constance C Danning Rebecca R Law Matthew H MH Sapkota Yadav Y Christofidou Paraskevi P Skarp Sini S Giri Ayush A Banasik Karina K Krassowski Michal M Lepamets Maarja M Marciniak Błażej B Nõukas Margit M Perro Danielle D Sliz Eeva E Sobalska-Kwapis Marta M Thorleifsson Gudmar G Topbas-Selcuki Nura F NF Vitonis Allison A Westergaard David D Arnadottir Ragnheidur R Burgdorf Kristoffer S KS Campbell Archie A Cheuk Cecilia S K CSK Clementi Caterina C Cook James J De Vivo Immaculata I DiVasta Amy A Dorien O O Donoghue Jacqueline F JF Edwards Todd T Fontanillas Pierre P Fung Jenny N JN Geirsson Reynir T RT Girling Jane E JE Harkki Paivi P Harris Holly R HR Healey Martin M Heikinheimo Oskari O Holdsworth-Carson Sarah S Hostettler Isabel C IC Houlden Henry H Houshdaran Sahar S Irwin Juan C JC Jarvelin Marjo-Riitta MR Kamatani Yoichiro Y Kennedy Stephen H SH Kepka Ewa E Kettunen Johannes J Kubo Michiaki M Kulig Bartosz B Kurra Venla V Laivuori Hannele H Laufer Marc R MR Lindgren Cecilia M CM MacGregor Stuart S Mangino Massimo M Martin Nicholas G NG Matalliotaki Charoula C Matalliotakis Michail M Murray Alison D AD Ndungu Anne A Nezhat Camran C Olsen Catherine M CM Opoku-Anane Jessica J Padmanabhan Sandosh S Paranjpe Manish M Peters Maire M Polak Grzegorz G Porteous David J DJ Rabban Joseph J Rexrode Kathyrn M KM Romanowicz Hanna H Saare Merli M Saavalainen Liisu L Schork Andrew J AJ Sen Sushmita S Shafrir Amy L AL Siewierska-Górska Anna A Słomka Marcin M Smith Blair H BH Smolarz Beata B Szaflik Tomasz T Szyłło Krzysztof K Takahashi Atsushi A Terry Kathryn L KL Tomassetti Carla C Treloar Susan A SA Vanhie Arne A Vincent Katy K Vo Kim C KC Werring David J DJ Zeggini Eleftheria E Zervou Maria I MI Adachi Sosuke S Buring Julie E JE Ridker Paul M PM D'Hooghe Thomas T Goulielmos George N GN Hapangama Dharani K DK Hayward Caroline C Horne Andrew W AW Low Siew-Kee SK Martikainen Hannu H Chasman Daniel I DI Rogers Peter A W PAW Saunders Philippa T PT Sirota Marina M Spector Tim T Strapagiel Dominik D Tung Joyce Y JY Whiteman David C DC Giudice Linda C LC Velez-Edwards Digna R DR Uimari Outi O Kraft Peter P Salumets Andres A Nyholt Dale R DR Mägi Reedik R Stefansson Kari K Becker Christian M CM Yurttas-Beim Piraye P Steinthorsdottir Valgerdur V Nyegaard Mette M Missmer Stacey A SA Montgomery Grant W GW Morris Andrew P AP Zondervan Krina T KT

Nature genetics 20230313 3

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes ...[more]

PMID: 36914876

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Project description:pain is one of the main symptoms of endometriosis and it has a deleterious effect on a patients' personal and social life. To date, the clinical management of pain includes prolonged medication use and, in some cases, surgery, both of which are disruptive events for patients. Hence, there is an urgency for the development of a sufficient non-invasive medical treatment. Inflammation is one of the causative factors of pain in endometriosis. It is well established that inflammatory mediators promote angiogenesis and interact with the sensory neurons inducing the pain signal; the threshold of pain varies and it depends on the state and location of the disease. The inhibition of inflammatory mediators' synthesis might offer a novel and effective treatment of the pain that is caused by inflammation in endometriosis. patients with endometriosis experience chronic pelvic pain, which is moderate to severe in terms of intensity. The objective of this systematic review is to highlight the inflammatory mediators that contribute to the induction of pain in endometriosis and present their biological mechanism of action. In addition, the authors aim to identify new targets for the development of novel treatments for chronic pelvic pain in patients with endometriosis. three databases (PubMed, Scopus, and Europe PMC) were searched in order to retrieve articles with the keywords 'inflammation, pain, and endometriosis' between the review period of 1 January 2016 to 31 December 2020. This review has been registered with PROSPERO (registry number: CRD42020171018). Eligibility Criteria: only original articles that presented the regulation of inflammatory mediators and related biological molecules in endometriosis and their contribution in the stimulation of pain signal were included. two authors independently extracted data from articles, using predefined criteria. the database search yielded 1871 articles, which were narrowed down to 56 relevant articles of interest according to the eligibility criteria. inflammatory factors that promote angiogenesis and neuroangiogenesis are promising targets for the treatment of inflammatory pain in endometriosis. Specifically, CXC chemokine family, chemokine fractalkine, and PGE2 have an active role in the induction of pain. Additionally, IL-1β appears to be the primary interleukin (IL), which stimulates the majority of the inflammatory factors that contribute to neuroangiogenesis along with IL-6. Finally, the role of Ninj1 and BDNF proteins needs further investigation.

Project description:Background and aimsWhile the prevalence of major depression is elevated among cannabis users, the role of genetics in this pattern of comorbidity is not clear. This study aimed to estimate the heritability of cannabis use and major depression, quantify the genetic overlap between these two traits and localize regions of the genome that segregate in families with cannabis use and major depression.DesignFamily-based univariate and bivariate genetic analysis.SettingSan Antonio, Texas, USA.ParticipantsGenetics of Brain Structure and Function study (GOBS) participants: 1284 Mexican Americans from 75 large multi-generation families and an additional 57 genetically unrelated spouses.MeasurementsPhenotypes of life-time history of cannabis use and major depression, measured using the semistructured MINI-Plus interview. Genotypes measured using ~1 M single nucleotide polymorphisms (SNPs) on Illumina BeadChips. A subselection of these SNPs were used to build multi-point identity-by-descent matrices for linkage analysis.FindingsBoth cannabis use [h2 = 0.614, P = 1.00 × 10-6 , standard error (SE) = 0.151] and major depression (h2 = 0.349, P = 1.06 × 10-5 , SE = 0.100) are heritable traits, and there is significant genetic correlation between the two (ρg = 0.424, P = 0.0364, SE = 0.195). Genome-wide linkage scans identify a significant univariate linkage peak for major depression on chromosome 22 [logarithm of the odds (LOD) = 3.144 at 2 centimorgans (cM)], with a suggestive peak for cannabis use on chromosome 21 (LOD = 2.123 at 37 cM). A significant pleiotropic linkage peak influencing both cannabis use and major depression was identified on chromosome 11 using a bivariate model (LOD = 3.229 at 112 cM). Follow-up of this pleiotropic signal identified a SNP 20 kb upstream of NCAM1 (rs7932341) that shows significant bivariate association (P = 3.10 × 10-5 ). However, this SNP is rare (seven minor allele carriers) and does not drive the linkage signal observed.ConclusionsThere appears to be a significant genetic overlap between cannabis use and major depression among Mexican Americans, a pleiotropy that appears to be localized to a region on chromosome 11q23 that has been linked previously to these phenotypes.

Dataset Information

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

Publications

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

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