Gallagher, C.S., Mäkinen, N., Harris, H.R. et al. Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis. Nat Commun 10, 4857 (2019). https://doi.org/10.1038/s41467-019-12536-4
Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis
|Author:||Gallagher, C. S.1; Makinen, N.2; Harris, H. R.3;|
1Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
2Harvard Med Sch, Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA.
3Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98109 USA.
4Univ Oxford, Wellcome Ctr Human Genet, Oxford OX3 7BN, England.
5Univ Oxford, John Radcliffe Hosp, Nuffield Dept Womens & Reprod Hlth, Endometriosis CaRe Ctr, Oxford OX3 9DU, England.
6Oulu Univ Hosp, Dept Obstet & Gynecol, Oulu, Finland.
7Univ Oulu, PEDEGO Res Unit, Oulu, Finland.
8Univ Oulu, Med Res Ctr Oulu, Oulu, Finland.
9Oulu Univ Hosp, Oulu, Finland.
10Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England.
11Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford OX3 7LF, England.
12Vanderbilt Univ, Dept Obstet & Gynecol, Inst Med & Publ Hlth,Med Ctr, Vanderbilt Genet Inst,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA.
13Vanderbilt Univ, Inst Med & Publ Hlth, Vanderbilt Genet Inst, Div Epidemiol,Dept Med,Med Ctr, Nashville, TN 37203 USA.
14Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia.
15Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge CB2 0QQ, England.
16Univ Oulu, Fac Med, Ctr Life Course Hlth Res, SF-90220 Oulu, Finland.
17Oulu Univ Hosp, Unit Primary Hlth Care, Oulu 90220, Finland.
18Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.
19Univ Oulu, Bioctr Oulu, SF-90220 Oulu, Finland.
20Brunel Univ London, Dept Life Sci, Coll Hlth & Life Sci, Uxbridge UB8 3PH, Middx, England.
21Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA.
22Harvard Med Sch, Div Preventat Med, Brigham & Womens Hosp, Boston, MA 02115 USA.
23Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA.
24Harvard Med Sch, Boston, MA 02115 USA.
25Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.
26QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4006, Australia.
27QIMR Berghofer Med Res Inst, Psychiat Genet, Brisbane, Qld 4006, Australia.
28Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4059, Australia.
29Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld 4059, Australia.
3023andMe, Mountain View, CA 94041 USA.
31Michigan State Univ, Coll Human Med, Dept Obstet Gynecol & Reprod Biol, Grand Rapids, MI 49503 USA.
32Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA.
33Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
34Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester Ctr Audiol & Deafness, Manchester M13 9PL, Lancs, England.
|Online Access:||PDF Full Text (PDF, 1.4 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe202003127979
|Publish Date:|| 2020-03-12
Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10−8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
The authors thank all of the women and their families who participated in WGHS, NFBC, QIMR, UK Biobank, 23andMe, and NHSII, and acknowledge the Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School. This study was supported by the U.S. National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grant HD060530 to C.C.M. C.C.M. is also supported by the NIHR Manchester Biomedical Research Centre. N.M. acknowledges support from the Academy of Finland (295693) and Orion Research Foundation. H.R.H. is supported by NIH K22 CA193860. T.F. is supported by the NIHR Biomedical Research Centre, Oxford. S.E.M. is supported by the National Health and Medical Research Council (NHMRC) Fellowship Scheme (1103623). We thank the Specialized Histopathology Core of the Dana-Farber/Harvard Cancer Center for FOXO1 immunostaining. The Dana-Farber/Harvard Cancer Center is supported in part by an NCI Cancer Center Support Grant P30 CA06516. Further acknowledgements are provided in Supplementary Note 1.
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