We investigated the functional significance of the GWS association at 1q13.2 by using the Web-based computational tool HaploReg, which facilitates identification of tagging SNPs in high linkage disequilibrium, and exploration of chromatin states, conservations, and transcription factor regulatory motif alterations.91,92
We describe the largest study to date capturing self-reported dysmenorrheic pain and findings from GWAS on pain severity. We identified one GWS association at 1q13.2 that colocalises with NGF, a neurotrophin linked to pain pathophysiology. Subjects carrying the risk allele reported more painful dysmenorrhea than did subjects without the risk allele, although the effect size was weak (increase of 0.1 points on a 4-point ordinal scale for increasing pain severity, explaining 0.48% of the observed variance).
We adjusted for 2 modulatory factors previously reported to impact on dysmenorrheic pain severity—age61,75 and BMI.38 Increased pain was correlated with younger age (P = 1.2 × 10−17) and lower BMI (P = 3.8 × 10−25). Effect estimates for age and BMI were only slightly stronger than the lead genetic variant, explaining 0.62% and 0.52% of the observed endpoint variance, respectively.
We observed enrichment for secondary dysmenorrheic conditions (including endometriosis, uterine fibroids, and PCOS) in our dysmenorrhea cohort. Endometriosis is a heritable disorder,84 with a few common risk factors identified.1,2,76,88 Analysis on surgically confirmed cases staged according to disease severity revealed that genetic factors account for a greater proportion of the risk of developing the most severe forms of endometriosis, which suggests that genetic factors may influence disease progression.63,68 In secondary dysmenorrhea associated with endometriosis, pain is caused by endometrial tissue formed on extrauterine locations, and benign invasion of endometrial tissue into the myometrium in those with adenomyosis.11 However, pain symptoms attributed to endometriosis occur in women without an endometriosis diagnosis, and for some individuals pain symptoms and severity correlate poorly with lesion characteristics.32,81 Uterine fibroids are benign tumours of the uterus that are often asymptomatic, but when diagnosed, patients often present with dysmenorrhea, excessive menstrual bleeding, bloating, and less frequently chronic pelvic pain.17 Evidence for genetic predisposition for uterine fibroids has been observed in both familial aggregation and twin studies.54 Polycystic ovarian syndrome is a common, heterogeneous endocrine disorder characterised by irregular menses, hyperandrogenism, and polycystic ovaries.79 Severe pain is not as common in PCOS; any pain experienced largely correlates with menstrual disturbances. Nevertheless, we also observed significant enrichment of PCOS in participants reporting extreme dysmenorrhea pain.
Shared genetic pleiotropy between dysmenorrhea, painful gynaecological conditions, depression, and other related disorders is an important area for investigation to further understand these conditions. Current GWAS data for these conditions have not identified a signal at the NGF locus.67,77 This might not be surprising as these genetic studies were designed to identify genetic factors that specifically influence risk of disease and not pain severity associated with disease.
In our study, pain severity was scored on an ordinal scale, a standard approach used for assessing pain in a variety of disorders including dysmenorrhea.55,86 Participant responses were normally distributed (Table 1), with 20.4% reporting extreme pain. A previous study capturing self-reported PD pain, reported that only 2% of participants experienced severe pain.93 The greater numbers reporting extreme pain in our cohort are likely due to our broader selection criteria, which did not exclude more painful secondary dysmenorrhea conditions. Previous studies similar in design to ours reported extreme pain in 15% to 22% of participants.71,72,83
Defining the biological basis behind this genetic association will further progress our understanding of dysmenorrhea pain pathophysiology. Our GWAS has identified a GWS locus at NGF, where associated variants colocalise with epigenetic regulatory regions, and are eQTLs for expression of a noncoding RNA that flanks the NGF locus. Although there is no evidence for a direct correlation of tagging SNPs and NGF expression, NGF remains the most plausible functional target for this pain-related phenotype. One possible mechanism for how a noncoding RNA might exert a functional impact on expression levels of another neurotrophin has been delineated by Modarresi et al.62 Brain-derived neurotrophic factor (BDNF) modulates pain signalling pathways at neuronal synapses.59 Expression of the BDNF gene is upregulated upon repression of an endogenous antisense transcript BDNF-AS, situated near and transcribed in the opposite orientation to BDNF in mice and humans. Repression of BDNF by BDNF-AS is not due to a direct knockdown interaction between transcripts but rather BDNF-AS transcription modulates local chromatin structure, altering repressive chromatin marks at the BDNF promoter and stimulating transcription of BDNF in a locus-specific manner. It remains to be determined whether a similar mechanism of posttranscriptional control mediated by endogenous antisense transcripts operates for other neurotrophins, including NGF.
The utility of assaying secreted NGF in fluids collected from tissues of interest has led to the suggestion that NGF could act as a clinical biomarker for chronic pain associated with inflammation,52 such as that typical in osteoarthritis. Likewise, levels of NGF measured in peritoneal tissues and fluid samples from endometriosis patients are higher in those with severer pain, which suggests that NGF production locally may contribute to endometriosis-associated pelvic pain.10,49 Despite the recent identification of BDNF Val66Met polymorphism (rs6265) as a risk factor for PD in a small cohort of Asians,53 peritoneal BDNF levels were not elevated in patients with endometriosis10 and we failed to observe significance of this variant in our dysmenorrhea pain GWAS (P = 0.94, effect = 0.0009 [−0.031 to 0.032], observed minor allele frequency = 18.6%).
NGF contributes to persistent pain states in adults acting as a peripheral mediator of inflammation leading to sensitization of pain pathways. In rodent models of cystitis and colitis, NGF causes reduced thresholds for activation of peripheral nociceptors to mechanical stimulation of visceral organs.23,24,34 Continued peripheral nociceptor input has been shown to be required for the maintenance of chronic pain conditions, and it is likely that NGF acts as a sensitizing factor in such states. Although the aetiology of dysmenorrhea remains unclear, uterine afferent sensitivity to menstrual contraction is one mechanism in which NGF signalling could result in altered pain perception.
How neurotrophins, and specifically NGF, contribute to visceral pain during endometriosis is unclear, but mechanisms involving sensitization of afferent pathways exposed in the peritoneal cavity or de novo sensory neurite outgrowth may contribute.6,10 Importantly, anti-NGF antibodies (such as fulranumab and tanezumab) and small-molecule TrkA inhibitors (including K252a) have proven effective in inhibiting increased peripheral mechanical sensitivity in models of other visceral inflammatory conditions, such as colitis and cystitis.23,34 Tanezumab is effective in treating chronic visceral pain, reducing pain in women with interstitial cystitis/painful bladder syndrome, but not men with prostatitis/chronic pelvic pain syndrome, which implicates that NGF may contribute to chronic pain conditions in a sex-specific manner.31,65
The value of Web-based surveys capturing phenotypic information on common traits in a large recontactable, genotyped cohort, has been demonstrated by the identification of novel genetic associations,28 and replication of findings previously identified in data sets compiled using stricter clinical diagnostic records.87 In this study, we relied solely on participants' assessment of their dysmenorrhea pain severity, and although this pain phenotype is captured by self-report in the clinic, there is still an inherent unreliability as the survey used was neither standardised nor validated, and is subject to recall bias.16 We acknowledge that the use of nonstandardised or validated self-reporting surveys may incur reporting error and anticipate a degree of bias of effect size estimates to the null, a caveat that should be considered when interpreting the effect size identified. The primary aim of GWAS is to discover new genetic predisposition factors. We demonstrate that a very large sample size was required to be informative when the trait in question is quantitative with a narrow dynamic range. Comparative dysmenorrhea studies currently lack sufficient sample sizes required to achieve power to replicate findings from this study (>3000 subjects would be required). Nevertheless, we encourage validation of these results in an independent cohort sufficiently detailed with phenotypic and clinical information, enabling further investigation to define the role of genetic predisposition factors on dysmenorrhea risk, classification, and comorbidities.
Further experimental validation exploring biological mechanisms are key to defining the role, if any, that NGF plays in dysmenorrhea pain severity (Fig. 6). If evidence is identified to support NGF as the causal gene, this opens the possibility for repurposing analgesics that target the NGF pathway for dysmenorrhea and related indications.
A. V. Jones, J. R.F. Hockley, C. Hyde, D. Gorman, J. Bilsland, G. McMurray, A. Sredic-Rhodes, P. J. Cox, and S. Scollen are current or past employees of and own stock or stock options in Pfizer, Inc. D. A. Hinds, Y. Hu, and N. A. Furlotte are current or past employees of and own stock or stock options in 23andMe, Inc.
This work was funded by Pfizer.
This publication is the work of the authors, and A. V. Jones and D. A. Hinds will serve as guarantors for the contents of this article.
Author contributions: A. V. Jones designed the study, analysed the data, and wrote the manuscript. J. R.F. Hockley analysed the data and wrote the manuscript. C. Hyde designed the study and analysed the data. D. Gorman, Y. Hu, N. A. Furlotte, and D. A. Hinds analysed the data. A. Sredic-Rhodes, J. Bilsland, and G. McMurray wrote the manuscript. S. Scollen and P. J. Cox designed and oversaw the study and wrote the manuscript. All authors reviewed the manuscript. P. J. Cox and S. Scollen share joint senior authorship.
The authors thank the research participants of 23andMe who answered surveys, as well as the employees of 23andMe, who together made this research possible.
Supplemental Digital Content
Supplemental Digital Content associated with this article can be found online at http://links.lww.com/PAIN/A320.
. Adachi S, Tajima A, Quan J, Haino K, Yoshihara K, Masuzaki H, Katabuchi H, Ikuma K, Suginami H, Nishida N, Kuwano R, Okazaki Y, Kawamura Y, Sasaki T, Tokunaga K, Inoue I, Tanaka K. Meta-analysis of genome-wide association scans for genetic susceptibility to endometriosis in Japanese population. J Hum Genet 2010;55:816–21.
. Albertsen HM, Chettier R, Farrington P, Ward K. Genome-wide association study
link novel loci to endometriosis. PLoS One 2013;8:e58257.
. Alonso C, Coe CL. Disruptions of social relationships accentuate the association between emotional distress and menstrual pain in young women. Health Psychol 2001;20:411–16.
. Altman G, Cain KC, Motzer S, Jarrett M, Burr R, Heitkemper M. Increased symptoms in female IBS patients with dysmenorrhea and PMS. Gastroenterol Nurs 2006;29:4–11.
. Andersch B, Milsom I. An epidemiologic study of young women with dysmenorrhea. Am J Obstet Gynecol 1982;144:655–60.
. Arnold J, Barcena de Arellano ML, Ruster C, Vercellino GF, Chiantera V, Schneider A, Mechsner S. Imbalance between sympathetic and sensory innervation in peritoneal endometriosis. Brain Behav Immun 2012;26:132–41.
. Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000;85:2434–8.
. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004;89:2745–9.
. Banikarim C, Chacko MR, Kelder SH. Prevalence and impact of dysmenorrhea on Hispanic female adolescents. Arch Pediatr Adolesc Med 2000;154:1226–9.
. Barcena de Arellano ML, Arnold J, Lang H, Vercellino GF, Chiantera V, Schneider A, Mechsner S. Evidence of neurotrophic events due to peritoneal endometriotic lesions. Cytokine 2013;62:253–61.
. Bird CC, McElin TW, Manalo-Estrella P. The elusive adenomyosis of the uterus–revisited. Am J Obstet Gynecol 1972;112:583–93.
. Burnett MA, Antao V, Black A, Feldman K, Grenville A, Lea R, Lefebvre G, Pinsonneault O, Robert M. Prevalence of primary dysmenorrhea in Canada. J Obstet Gynaecol Can 2005;27:765–70.
. Campbell MA, McGrath PJ. Use of medication by adolescents for the management of menstrual discomfort. Arch Pediatr Adolesc Med 1997;151:905–13.
. Campbell MA, McGrath PJ. Non-pharmacologic strategies used by adolescents for the management of menstrual discomfort. Clin J Pain 1999;15:313–20.
. Carithers LJ, Moore HM. The genotype-tissue expression (GTEx) project. Biopreserv Biobank 2015;13:307–8.
. Chen CX, Kwekkeboom KL, Ward SE. Self-report pain and symptom measures for primary dysmenorrhoea: a critical review. Eur J Pain 2015;19:377–91.
. Ciavattini A, Di Giuseppe J, Stortoni P, Montik N, Giannubilo SR, Litta P, Islam MS, Tranquilli AL, Reis FM, Ciarmela P. Uterine fibroids: pathogenesis and interactions with endometrium and endomyometrial junction. Obstet Gynecol Int 2013;2013:173184.
. Coco AS. Primary dysmenorrhea. Am Fam Physician 1999;60:489–96.
. Consortium C. Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature 2015;523:588–91.
. Consortium G. The genotype-tissue expression (GTEx) project. Nat Genetics 2013;45:580–5.
. Consortium G. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 2015;348:648–60.
. Daniels K, Daugherty J, Jones J. Current contraceptive status among women aged 15-44: United States, 2011-2013. NCHS Data Brief 2014:1–8.
. Delafoy L, Gelot A, Ardid D, Eschalier A, Bertrand C, Doherty AM, Diop L. Interactive involvement of brain derived neurotrophic factor, nerve growth factor, and calcitonin gene related peptide in colonic hypersensitivity in the rat. Gut 2006;55:940–5.
. Dmitrieva N, McMahon SB. Sensitisation of visceral afferents by nerve growth factor in the adult rat. PAIN 1996;66:87–97.
. Dorn LD, Negriff S, Huang B, Pabst S, Hillman J, Braverman P, Susman EJ. Menstrual symptoms in adolescent girls: association with smoking, depressive symptoms, and anxiety. J Adolesc Health 2009;44:237–43.
. Durain D. Primary dysmenorrhea: assessment and management update. J Midwifery Womens Health 2004;49:520–8.
. Ehlers S, Gillberg C. The epidemiology of Asperger syndrome. A total population study. J Child Psychol Psychiatry 1993;34:1327–50.
. Eriksson N, Macpherson JM, Tung JY, Hon LS, Naughton B, Saxonov S, Avey L, Wojcicki A, Pe'er I, Mountain J. Web-based, participant-driven studies yield novel genetic associations for common traits. PLoS Genet 2010;6:e1000993.
. Ernst J, Kellis M. Large-scale imputation of epigenomic datasets for systematic annotation of diverse human tissues. Nat Biotechnol 2015;33:364–76.
. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 1997;24:235–58.
. Evans RJ, Moldwin RM, Cossons N, Darekar A, Mills IW, Scholfield D. Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. J Urol 2011;185:1716–21.
. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update 2005;11:595–606.
. Galea S, Nandi A, Vlahov D. The epidemiology of post-traumatic stress disorder after disasters. Epidemiol Rev 2005;27:78–91.
. Guerios SD, Wang ZY, Boldon K, Bushman W, Bjorling DE. Blockade of NGF and trk receptors inhibits increased peripheral mechanical sensitivity accompanying cystitis in rats. Am J Physiol Regul Integr Comp Physiol 2008;295:R111–122.
. Gupta S, Jose J, Manyonda I. Clinical presentation of fibroids. Best Pract Res Clin Obstet Gynaecol 2008;22:615–26.
. Harel Z. Cyclooxygenase-2 specific inhibitors in the treatment of dysmenorrhea. J Pediatr Adolesc Gynecol 2004;17:75–9.
. Harel Z. Dysmenorrhea in adolescents and young adults: from pathophysiology to pharmacological treatments and management strategies. Expert Opin Pharmacother 2008;9:2661–72.
. Harlow SD, Park M. A longitudinal study of risk factors for the occurrence, duration and severity of menstrual cramps in a cohort of college women. Br J Obstet Gynaecol 1996;103:1134–42.
. Howe AS, Buttenschon HN, Bani-Fatemi A, Maron E, Otowa T, Erhardt A, Binder EB, Gregersen NO, Mors O, Woldbye DP, Domschke K, Reif A, Shlik J, Koks S, Kawamura Y, Miyashita A, Kuwano R, Tokunaga K, Tanii H, Smoller JW, Sasaki T, Koszycki D, De Luca V. Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways. Mol Psychiatry 2016;21:665–79.
. Hudson JI, Hiripi E, Pope HG Jr, Kessler RC. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry 2007;61:348–58.
. Iacovides S, Avidon I, Baker FC. What we know about primary dysmenorrhea today: a critical review. Hum Reprod Update 2015;21:762–78.
. Jamieson DJ, Steege JF. The prevalence of dysmenorrhea, dyspareunia, pelvic pain, and irritable bowel syndrome in primary care practices. Obstet Gynecol 1996;87:55–8.
. Janssen EB, Rijkers AC, Hoppenbrouwers K, Meuleman C, D'Hooghe TM. Prevalence of endometriosis diagnosed by laparoscopy in adolescents with dysmenorrhea or chronic pelvic pain: a systematic review. Hum Reprod Update 2013;19:570–82.
. Jensen DV, Andersen KB, Wagner G. Prostaglandins in the menstrual cycle of women. A review. Dan Med Bull 1987;34:178–82.
. Jones AE. Managing the pain of primary and secondary dysmenorrhoea. Nurs Times 2004;100:40–3.
. Ju H, Jones M, Mishra G. The prevalence and risk factors of dysmenorrhea. Epidemiol Rev 2014;36:104–13.
. Ju H, Jones M, Mishra GD. A U-Shaped relationship between body mass index and dysmenorrhea: a longitudinal study. PLoS One 2015;10:e0134187.
. Juang CM, Yen MS, Twu NF, Horng HC, Yu HC, Chen CY. Impact of pregnancy on primary dysmenorrhea. Int J Gynaecol Obstet 2006;92:221–7.
. Kajitani T, Maruyama T, Asada H, Uchida H, Oda H, Uchida S, Miyazaki K, Arase T, Ono M, Yoshimura Y. Possible involvement of nerve growth factor in dysmenorrhea and dyspareunia associated with endometriosis. Endocr J 2013;60:1155–64.
. Katerndahl DA, Realini JP. Lifetime prevalence of panic states. Am J Psychiatry 1993;150:246–9.
. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:617–27.
. Kumar V, Mahal BA. NGF–the TrkA to successful pain treatment. J Pain Res 2012;5:279–87.
. Lee LC, Tu CH, Chen LF, Shen HD, Chao HT, Lin MW, Hsieh JC. Association of brain-derived neurotrophic factor gene Val66Met polymorphism with primary dysmenorrhea. PLoS One 2014;9:e112766.
. Ligon AH, Morton CC. Leiomyomata: heritability and cytogenetic studies. Hum Reprod Update 2001;7:8–14.
. Ma YX, Ma LX, Liu XL, Ma YX, Lv K, Wang D, Liu JP, Xing JM, Cao HJ, Gao SZ, Zhu J. A comparative study on the immediate effects of electroacupuncture at Sanyinjiao (SP6), Xuanzhong (GB39) and a non-meridian point, on menstrual pain and uterine arterial blood flow, in primary dysmenorrhea patients. Pain Med 2010;11:1564–75.
. Mannix LK. Menstrual-related pain conditions: dysmenorrhea and migraine. J Womens Health (Larchmt) 2008;17:879–91.
. Marcus SM, Heringhausen JE. Depression in childbearing women: when depression complicates pregnancy. Prim Care 2009;36:151–65. ix.
. McLean CP, Asnaani A, Litz BT, Hofmann SG. Gender differences in anxiety disorders: prevalence, course of illness, comorbidity and burden of illness. J Psychiat Res 2011;45:1027–35.
. Merighi A, Salio C, Ghirri A, Lossi L, Ferrini F, Betelli C, Bardoni R. BDNF as a pain modulator. Prog Neurobiol 2008;85:297–317.
. Messias EL, Chen CY, Eaton WW. Epidemiology of schizophrenia: review of findings and myths. Psychiatr Clin North Am 2007;30:323–38.
. Messing K, Saurel-Cubizolles MJ, Bourgine M, Kaminski M. Factors associated with dysmenorrhea among workers in French poultry slaughterhouses and canneries. J Occup Med 1993;35:493–500.
. Modarresi F, Faghihi MA, Lopez-Toledano MA, Fatemi RP, Magistri M, Brothers SP, van der Brug MP, Wahlestedt C. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol 2012;30:453–9.
. Montgomery GW, Zondervan KT, Nyholt DR. The future for genetic studies in reproduction. Mol Hum Reprod 2014;20:1–14.
. Ng TP, Tan NC, Wansaicheong GK. A prevalence study of dysmenorrhoea in female residents aged 15-54 years in Clementi Town, Singapore. Ann of the Acad Med Singapore 1992;21:323–7.
. Nickel JC, Mills IW, Crook TJ, Jorga A, Smith MD, Atkinson G, Krieger JN. Tanezumab reduces pain in women with interstitial cystitis/bladder pain syndrome and patients with nonurological associated somatic syndromes. J Urol 2016;195:942–8.
. Noble RE. Depression in women. Metabolism 2005;54(5 suppl 1):49–52.
. Nyholt DR, Low SK, Anderson CA, Painter JN, Uno S, Morris AP, MacGregor S, Gordon SD, Henders AK, Martin NG, Attia J, Holliday EG, McEvoy M, Scott RJ, Kennedy SH, Treloar SA, Missmer SA, Adachi S, Tanaka K, Nakamura Y, Zondervan KT, Zembutsu H, Montgomery GW. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat Genet 2012;44:1355–9.
. Painter JN, Anderson CA, Nyholt DR, Macgregor S, Lin J, Lee SH, Lambert A, Zhao ZZ, Roseman F, Guo Q, Gordon SD, Wallace L, Henders AK, Visscher PM, Kraft P, Martin NG, Morris AP, Treloar SA, Kennedy SH, Missmer SA, Montgomery GW, Zondervan KT. Genome-wide association study
identifies a locus at 7p15.2 associated with endometriosis. Nat Genet 2011;43:51–4.
. Parazzini F, Tozzi L, Mezzopane R, Luchini L, Marchini M, Fedele L. Cigarette smoking, alcohol consumption, and risk of primary dysmenorrhea. Epidemiology 1994;5:469–72.
. Parveen N, Majeed R, Zehra N, Rajar U, Munir AA. Attitude and knowledge of medical students of Isra university about dysmenorrhoea and its treatment. J Ayub Med Coll Abbottabad 2009;21:159–62.
. Patel V, Tanksale V, Sahasrabhojanee M, Gupte S, Nevrekar P. The burden and determinants of dysmenorrhoea: a population-based survey of 2262 women in Goa, India. BJOG 2006;113:453–63.
. Pitts MK, Ferris JA, Smith AM, Shelley JM, Richters J. Prevalence and correlates of three types of pelvic pain in a nationally representative sample of Australian women. Med J Aust 2008;189:138–43.
. Proctor M, Farquhar C. Diagnosis and management of dysmenorrhoea. BMJ 2006;332:1134–8.
. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, Boehnke M, Abecasis GR, Willer CJ. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 2010;26:2336–7.
. Pullon S, Reinken J, Sparrow M. Prevalence of dysmenorrhoea in Wellington women. N Z Med J 1988;101:52–4.
. Rahmioglu N, Macgregor S, Drong AW, Hedman AK, Harris HR, Randall JC, Prokopenko I, Nyholt DR, Morris AP, Montgomery GW, Missmer SA, Lindgren CM, Zondervan KT. Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci. Hum Mol Genet 2015;24:1185–99.
. Ripke S, Wray NR, Lewis CM, Hamilton SP, Weissman MM, Breen G, Byrne EM, Blackwood DH, Boomsma DI, Cichon S, Heath AC, Holsboer F, Lucae S, Madden PA, Martin NG, McGuffin P, Muglia P, Noethen MM, Penninx BP, Pergadia ML, Potash JB, Rietschel M, Lin D, Muller-Myhsok B, Shi J, Steinberg S, Grabe HJ, Lichtenstein P, Magnusson P, Perlis RH, Preisig M, Smoller JW, Stefansson K, Uher R, Kutalik Z, Tansey KE, Teumer A, Viktorin A, Barnes MR, Bettecken T, Binder EB, Breuer R, Castro VM, Churchill SE, Coryell WH, Craddock N, Craig IW, Czamara D, De Geus EJ, Degenhardt F, Farmer AE, Fava M, Frank J, Gainer VS, Gallagher PJ, Gordon SD, Goryachev S, Gross M, Guipponi M, Henders AK, Herms S, Hickie IB, Hoefels S, Hoogendijk W, Hottenga JJ, Iosifescu DV, Ising M, Jones I, Jones L, Jung-Ying T, Knowles JA, Kohane IS, Kohli MA, Korszun A, Landen M, Lawson WB, Lewis G, Macintyre D, Maier W, Mattheisen M, McGrath PJ, McIntosh A, McLean A, Middeldorp CM, Middleton L, Montgomery GM, Murphy SN, Nauck M, Nolen WA, Nyholt DR, O'Donovan M, Oskarsson H, Pedersen N, Scheftner WA, Schulz A, Schulze TG, Shyn SI, Sigurdsson E, Slager SL, Smit JH, Stefansson H, Steffens M, Thorgeirsson T, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Volzke H, Weilburg JB, Willemsen G, Zitman FG, Neale B, Daly M, Levinson DF, Sullivan PF. A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 2013;18:497–511.
. Shaver JL, Wilbur J, Robinson FP, Wang E, Buntin MS. Women's health issues with fibromyalgia syndrome. J Womens Health (Larchmt) 2006;15:1035–45.
. Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol 2014;6:1–13.
. Sit D. Women and bipolar disorder across the life span. J Am Med Womens Assoc 2004;59:91–100.
. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update 2011;17:327–46.
. Sundell G, Milsom I, Andersch B. Factors influencing the prevalence and severity of dysmenorrhoea in young women. Br J Obstet Gynaecol 1990;97:588–94.
. Tavallaee M, Joffres MR, Corber SJ, Bayanzadeh M, Rad MM. The prevalence of menstrual pain and associated risk factors among Iranian women. J Obstet Gynaecol Res 2011;37:442–51.
. Treloar SA, O'Connor DT, O'Connor VM, Martin NG. Genetic influences on endometriosis in an Australian twin sample. sueT@qimr.edu.au. Fertil Steril 1999;71:701–10.
. Tu CH, Niddam DM, Yeh TC, Lirng JF, Cheng CM, Chou CC, Chao HT, Hsieh JC. Menstrual pain is associated with rapid structural alterations in the brain. PAIN 2013;154:1718–24.
. Tugay N, Akbayrak T, Demirturk F, Karakaya IC, Kocaacar O, Tugay U, Karakaya MG, Demirturk F. Effectiveness of transcutaneous electrical nerve stimulation and interferential current in primary dysmenorrhea. Pain Med 2007;8:295–300.
. Tung JY, Do CB, Hinds DA, Kiefer AK, Macpherson JM, Chowdry AB, Francke U, Naughton BT, Mountain JL, Wojcicki A, Eriksson N. Efficient replication of over 180 genetic associations with self-reported medical data. PLoS One 2011;6:e23473.
. Uno S, Zembutsu H, Hirasawa A, Takahashi A, Kubo M, Akahane T, Aoki D, Kamatani N, Hirata K, Nakamura Y. A genome-wide association study
identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat Genet 2010;42:707–10.
. Unsal A, Ayranci U, Tozun M, Arslan G, Calik E. Prevalence of dysmenorrhea and its effect on quality of life among a group of female university students. Ups J Med Sci 2010;115:138–45.
. Vincent K, Warnaby C, Stagg CJ, Moore J, Kennedy S, Tracey I. Dysmenorrhoea is associated with central changes in otherwise healthy women. PAIN 2011;152:1966–75.
. Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 2012;40:D930–4.
. Ward LD, Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res 2016;44:D877–81.
. Weissman AM, Hartz AJ, Hansen MD, Johnson SR. The natural history of primary dysmenorrhoea: a longitudinal study. BJOG 2004;111:345–52.
. Williams L, Jacka F, Pasco J, Henry M, Dodd S, Nicholson G, Kotowicz M, Berk M. The prevalence of mood and anxiety disorders in Australian women. Australas Psychiatry 2010;18:250–5.
. Wong LP, Khoo EM. Dysmenorrhea in a multiethnic population of adolescent Asian girls. Int J Gynaecol Obstet 2010;108:139–42.
. Yunus MB. Fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes. Semin Arthritis Rheum 2007;36:339–56.
. Zahradnik HP, Hanjalic-Beck A, Groth K. Nonsteroidal anti-inflammatory drugs and hormonal contraceptives for pain relief from dysmenorrhea: a review. Contraception 2010;81:185–96.