Zondervan group

Research overview

Our group focuses on the integration of genetic, molecular, and environmental epidemiological research methods in uncovering the aetiology of benign women's health conditions that carry a substantial public health burden. We are based both at the Wellcome Centre for Human Genetics (WCHG) and the Nuffield Dept of Women's and Reproductive Health in Oxford where Prof Zondervan is Co-Director of the Oxford Endometriosis CaRe Centre.

Endometriosis is a common, poorly understood chronic inflammatory condition in women of reproductive age, involving the presence of endometrial-like cells in extra-uterine pelvic sites. The condition causes pain and sub-fertility; is estimated to affect 5-10% of women in their reproductive years (176 million women worldwide and 1.5 million in the UK); has limited diagnostic and treatment options; and has a major impact on health-related quality of life of sufferers and their families.

Heritable factors are involved in endometriosis risk. Identifying which DNA variants underlie this heritability will improve our understanding of pathogenesis and inform treatment development. We lead the International Endometriosis Genome Consortium (IEC) in which we are conducting the largest collaborative genome-wide association studies (GWAS) of endometriosis to date (e.g. Nature Genetics 2011& 2012; Nature Communications 2017). The consortium has recently expanded to 16 research centres contributing GWAS data on over 60,000 women with endometriosis.

In addition to continued genetic discovery work, we have led a large global initiative in endometriosis research to develop standardised deep phenotyping tools and sample collection protocols (WERF EPHect); these are implemented so far in 18 endometriosis research centres worldwide. In the Endometriosis CaRe centre we are currently using WERF EPHect-compliant data and samples from women attending our centre to explore what biological pathways implicated genetic variants 'signpost', and how findings can aid discovery of novel treatment targets and biomarkers.

To this end, within the Centre we have established a programme of translational research and have very strong links with industry partners to allow translation of our research findings, for example through our Bayer AG - Oxford Scientific Alliance in Gynaecological Therapies. This work is made possible through the much appreciated involvement of many women with and without the disease, who contribute information and samples to our studies and through our many collaborations internationally.

 

Selected recent publications

For a full list: Publications

Rahmioglu N, Drong AW, Lockstone H, Tapmeier T, Hellner K, Saare M, Laisk-Podar T, Dew C, Tough E, Nicholson G, Peters M, Morris AP, Lindgren CM, Becker CM, Zondervan KT. Variability of genome-wide DNA methylation and mRNA expression profiles in reproductive and endocrine disease related tissues. Epigenetics. 2017 Nov 3: doi: 10.1080/15592294.2017.

Sapkota Y, Steinthorsdottir V, Morris AP, Fassbender A, Rahmioglu N, De Vivo I, Buring JE, Zhang F, Edwards TL, Jones S, O D, Peterse D, Rexrode KM, Ridker PM, Schork AJ, MacGregor S, Martin NG, Becker CM, Adachi S, Yoshihara K, Enomoto T, Takahashi A, Kamatani Y, Matsuda K, Kubo M, Thorleifsson G, Geirsson RT, Thorsteinsdottir U, Wallace LM; iPSYCH-SSI-Broad Group, Yang J, Velez Edwards DR, Nyegaard M, [Low SK*, Zondervan KT*, Missmer SA*, D'Hooghe T*, Montgomery GW*, Chasman DI*, Stefansson K*, Tung JY*, Nyholt DR*]. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nature Commun. 2017;8:15539

Uimari O, Rahmioglu N, Nyholt DR, Vincent K, Missmer SA, Becker CM, Morris AP, Montgomery G, Zondervan KT. Genome-wide genetic analyses highlight mitogen-activated protein kinase (MAPK) signaling in the pathogenesis of endometriosis. Human Reproduction 2017;32:780–793

Rogers PA, Adamson GD, Al-Jefout M, Becker CM, D'Hooghe TM, Dunselman GA, Fazleabas A, Giudice LC, Horne AW, Hull ML, Hummelshoj L, Missmer SA, Montgomery GW, Stratton P, Taylor RN, Rombauts L, Saunders PT, Vincent K, Zondervan KT for the WES/WERF Consortium. Research Priorities for Endometriosis: Recommendations from a Global Consortium of Investigators in Endometriosis. Reprod Sci. 2017;24:202-226.

Zondervan KT, Rahmioglu N, Morris AP, Nyholt DR, Montgomery GW, Becker CM, Missmer SA. Beyond Endometriosis Genome-Wide Association Study: From Genomics to Phenomics to the Patient. Semin Reprod Med. 2016;34:242-54.

Lu Y, Cuellar-Partida G, Painter JN, Nyholt DR; Australian Ovarian Cancer Study; International Endogene Consortium (IEC), Morris AP, Fasching PA, Hein A, Burghaus S, Beckmann MW, Lambrechts D, Van Nieuwenhuysen E, Vergote I, Vanderstichele A, Doherty JA, [100+ authors], Risch HA, Goode EL, Schildkraut JM, Webb PM, Pearce CL, Berchuck A, Pharoah PD, Montgomery GW, Zondervan KT, Chenevix-Trench G, McGregor S. Shared genetics underlying epidemiological association between endometriosis and ovarian cancer. Hum Mol Genet. 2015; 24:5955-64

Rahmioglu N, Macgregor S, Drong AW, Hedman AK, Harris HR, Randall JC, Prokopenko I, The International EndoGene Consortium (IEC), The GIANT Consortium, 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

Becker CM, Laufer MR, Stratton P, Hummelshoj L, Missmer SA*, Zondervan KT*, Adamson GD*, for the WERF EPHect Working Group. WERF Endometriosis Phenome and Biobanking Harmonization Project (EPHect): I. Surgical phenotype data collection in endometriosis research. Fertil Steril. 2014;102:1213-1222. Series of four papers.

Rahmioglu N, Nyholt DR, Morris AP, Missmer SA, Montgomery GW, Zondervan KT. Genetic variants underlying endometriosis risk: insights from eight genome-wide association and replication datasets in 11,000 cases and 32,000 controls. Hum Reprod Update 2014; 20:702-16.

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. Nature Genetics 2012;44:1355-9

Painter JN, Anderson CA, Nyholt DR, Macgregor S, Lin J, Lee SH, Lambert A, Zhao Z, 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. Nature Genetics 2011;43:51-4

Grundberg E, Small KS, Hedman AK, Nica AC, Buil A, Keildson S, Bell JT, Yang T-P, Barrett A, Nisbet J,  Sekowska M, Wilk A,  Shin S-Y, Glass D, Travers M,  Min JL, Ring S, Ho K, Thorleifsson G, Kong A, Thorsteindottir U, Ainali BC, Dimas AS, Hassanali N, Ingle C, Knowles D, Krestyaninova M, Lowe CE, Meduri E, Di Meglio P,  Montgomery SB, Parts L, Potter S, Surdulescu G, Tsaprouni L, Tsoka S, Bataille V, Durbin R, Nestle FO, O’Rahilly S, Soranzo N, Lindgren SM, Zondervan KT, Ahmadi K, Schadt EE, Stefansson K, Davey Smith G, McCarthy MI, Deloukas P, Dermitzakis ET, Spector TD, for the MuTHER consortium. Mapping cis and trans regulatory effects across multiple tissues in twins: the MuTHER Study. Nature Genetics 2012;44:1084-1089.

Min JL, Nicholson G, Halgrimsdottir I, Almstrup K, Petri A, Barrett A, Travers M, Rayner NW, Mägi R, Pettersson FH, Broxholme J, Neville MJ, Wills QF, Cheeseman J; The GIANT Consortium; The MolPAGE Consortium, Allen M, Holmes CC, Spector TD, Fleckner J, McCarthy MI, Karpe F, Lindgren CM, Zondervan KT. Coexpression Network Analysis in Abdominal and Gluteal Adipose Tissue Reveals Regulatory Genetic Loci for Metabolic Syndrome and Related Phenotypes. PLoS Genetics 2012;8:e1002505

Nnoaham KE, Hummelshoj L, Webster P, d'Hooghe T, de Cicco Nardone F, de Cicco Nardone C, Jenkinson C, Kennedy SH, Zondervan KT; World Endometriosis Research Foundation Global Study of Women's Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertility & Sterility 2011;96:366-373.

Funding sources

The Wellcome Trust; Medical Reseach Council, EU, US National Institutes of Health; World Endometriosis Research Foundation; Industry