Genomics of reproductive disorders

Identifying genetic risk factors for reproductive disorders

Genetic factors contribute to risk for many common diseases including reproductive disorders.

Professor Montgomery is leading a team of scientists using genetics and genomics to find factors explaining variation in reproductive traits and increasing risk for reproductive diseases.

One of these disorders is endometriosis where tissue similar to the normal uterine lining grows and invades areas around the pelvis. It creates scar tissue that impedes the function of the organs by reducing their mobility. It causes serious pain and in many cases, infertility.

Group leader

Professor Grant Montgomery

Professor Grant Montgomery

Group Leader, Genomics of reproductive disorders

Director, UQ Genome Innovation Hub

+61 7 3346 2612
  IMB Researcher Profile
UQ Genome Innovation Hub

We know little about endometriosis and like many complex diseases, the contributing environmental and genetic risk factors are like a giant jigsaw puzzle.

“Multiple genetic variants and environmental risk factors contribute incrementally to increasing risk,” Professor Montgomery said.

Professor Montgomery’s research team analyses genetic markers from across the genome to determine the genomic regions associated with risk.

The next step is to search through these genomic regions to identify the target genes in each region and how altered gene regulation increases disease risk. 

Understanding the other 50% - the environmental factors

How do you identify environmental influences on a person’s disease risk? It’s a vital piece of the puzzle because while you can’t change genetics, you can influence environmental factors. Professor Montgomery may have a solution.

“Our interaction with environmental factors can leave information on our DNA. If the environmental signature is there we could work backwards – finding the signatures and then designing experiments to determine what caused them.”

If this methodology works, it will pioneer a method for exploring many common diseases, all of which have a combination of genetic and environmental risk factors.

Caption: Genetic and genomic studies to identify target genes and functional effects of genetic variants that increase endometriosis risk.
Credit: Fung et al., DOI 10.1095/biolreprod.114.126458

Using systems genomics to better understand reproductive disorders

We use systems genomics and analysis of multiple genomics datasets to search through genomic risk regions to identify the target genes in each region and how altered gene regulation increases disease risk. The research applies recent advances in genomics, statistics and computing to better understand the different molecular mechanisms by which genetic markers influence disease risk and development.

My group studies the genetic factors contributing to reproductive disorders and their functional consequences to translate knowledge gained from the genetic studies for disease biology and clinical outcomes.

Genetic factors contributing to endometriosis risk

We are analysing genetic factors contributing to endometriosis risk. Our recent studies, in collaboration with 10 international groups, identified 14 genomic regions associated with endometriosis. We are participating in the next generation of genome-wide association studies and the analysis of overlap with other diseases, including migraine, ovarian cancer, and endometrial cancer.  

Genetic regulation of gene expression

Expression of many genes is under genetic control and many genetic factors contributing to common disease are located in regulatory regions of the genome affecting gene expression. Our research aims to better understand the genetic and epigenetic regulation of gene expression especially in the endometrium. This is an important tissue, essential for establishment and maintenance of pregnancy.

Expression of many genes in endometrium show dynamic changes across the menstrual cycle. Following analyses of gene expression and RNA sequencing studies in endometrium we have identified genetic control of expression and associations with reproductive traits and disorders.

We continue to explore cell-type specific regulation using the latest RNA-sequencing and single-cell sequencing technologies to identify cell-type specific genetic contributions to the pathogenesis of reproductive disorders.

Functional studies in endometriosis

We are conducting functional studies in endometrium and cell lines to identify the critical genes and functional consequences of the known genetic factors increasing endometriosis risk. This includes genetic effects on gene expression and alternative splicing in regions associated with the disease, studies of chromatin looping between causal variants and gene promoters and developing cell based models for genetic and functional studies in the endometrium.

Epigenetic studies

We are part of an international consortium to study epigenetic control of gene expression in endometrium and will be responsible for the joint analysis of DNA methylation data and integration with gene expression data from the same samples and with our genome-wide association results.

System Genomics

Professor Montgomery’s lab has generated one of the largest multi-omic datasets for human endometrium providing a valuable resource to help identify gene targets, pathways and networks regulating female reproductive traits and diseases. His team use a range of experimental and statistical approaches to integrate these various datasets (genetics, gene expression, methylation) to better understand the molecular architecture of disease.

Data Tools

We have developed ShinyApps, light-weight software tools, for searching datasets generated by our group. This includes data on the genetic regulation of gene expression (expression quantitative trait loci; eQTLs) and methylation (methylation quantitative trait loci; mQTLs) in human endometrium and blood. The apps were written by Dr Samuel Lukowski.

The Endo eQTL RNAseq browser is a database of eQTL results from an endometrial RNA-sequencing dataset on 206 women.

The Endometrial tissue eQTL browser v2 is a database of eQTL results from an endometrial gene expression array dataset on 229 women. See published research for further details.

The endometrial mQTL browser is a database of mQTL results from an endometrial DNA methylation dataset on 66 women. The blood mQTL browser is a database of mQTL results from a blood DNA methylation dataset on the same 66 women. See published research for further details.

Research title: Genomics of reproductive disorders

Summary of research interests: We use genetic approaches to discover critical genes and pathways increasing risk for complex diseases. Follow-up genomic studies aim to understand how these genetic differences regulate gene expression and epigenetics to alter disease risk. A major focus is women’s health and the pathogenesis of endometriosis. We have identified genomic regions strongly associated with increased endometriosis risk and are analyzing gene expression and methylation patterns in the endometrium to understand how these genetic variants contribute to increased disease risk. Endometriosis is associated with other reproductive traits and diseases including ovarian cancer and we also study the mechanisms of shared genetic risk. 

Traineeships, Honours and PhD projects include

  • Analysis of gene expression in the human endometrium and endometrial cell types
  • Analysis of genomic regions associated with endometriosis risk and other diseases
  • Genetic control of methylation patterns in the endometrium and other tissues.
  • Multi-omic data integration to identify target genes and pathways for reproductive disorders.

Contact: Professor Grant Montgomery

+61 7 3346 2054


Tissue specific regulation of transcription in endometrium and association with disease.
Mortlock, S., Kendarsari, R.I., Fung, J.N., Gibson, G., Yang, F., Restuadi, R., Girling, J.E., Holdsworth-Carson, S.J., Teh, W.T., Lukowski, S.W., Healey, M., Qi, T., Rogers, P.A.W., Yang, J., McKinnon, B. and Montgomery, G.W. (2020)
Hum Reprod: (in press).

The role of the endocannabinoid system in aetiopathogenesis of endometriosis: A potential therapeutic target.
Tanaka, K., Mayne, L., Khalil, A., Baartz, D., Eriksson, L., Mortlock, S.A., Montgomery, G., McKinnon, B. and Amoako, A.A. (2019)
European Journal of Obstetrics Gynecology and Reproductive Biology 244: 87-94.

Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases.
Mortlock, S., Restuadi, R., Levien, R., Girling, J.E., Holdsworth-Carson, S.J., Healey, M., Zhu, Z., Qi, T., Wu, Y., Lukowski, S.W., Rogers, P.A.W., Yang, J., McRae, A.F., Fung, J.N. and Montgomery, G.W. (2019)
Clinical Epigenetics 11: 49.

The Association of Sonographic Evidence of Adenomyosis with Severe Endometriosis and Gene Expression in Eutopic Endometrium.
Dior, U.P., Nisbet, D., Fung, J.N., Foster, G., Healey, M., Montgomery, G.W., Rogers, P.A.W., Holdsworth-Carson, S.J. and Girling, J.E. (2019)
Journal of Minimallly Invasive Gynecology 26: 941-948.

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.
Gallagher, C.S., Makinen, N., Harris, H.R., Rahmioglu, N., Uimari, O., Cook, J.P., et al., (2019)
Nat Commun 10: 4857.

Genetic overlap between endometriosis and endometrial cancer: evidence from cross-disease genetic correlation and GWAS meta-analyses.
Painter, J.N., O'Mara, T.A., Morris, A.P., Cheng, T.H.T., Gorman, M., Martin, L., et al., (2018)
Cancer Med 7: 1978-1987.

Genetic regulation of disease risk and endometrial gene expression highlights potential target genes for endometriosis and polycystic ovarian syndrome.
Fung, J.N., Mortlock, S., Girling, J.E., Holdsworth-Carson, S.J., Teh, W.T., Zhu, Z., Lukowski, S.W., McKinnon, B.D., McRae, A., Yang, J., Healey, M., Powell, J.E., Rogers, P.A.W. and Montgomery, G.W. (2018)
Science Reports 8: 11424.

Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry.
Sapkota, Y., Vivo, I., Steinthorsdottir, V., Fassbender, A., Bowdler, L., Buring, J.E., Edwards, T.L., Jones, S., O, D., Peterse, D., Rexrode, K.M., Ridker, P.M., Schork, A.J., Thorleifsson, G., Wallace, L.M., i, P.-S.S.I.B.G., Kraft, P., Morris, A.P., Nyholt, D.R., Edwards, D.R.V., Nyegaard, M., D'Hooghe, T., Chasman, D.I., Stefansson, K., Missmer, S.A. and Montgomery, G.W. (2017)
Scientific Reports 7: 11380.

Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry.
Sapkota, Y., Steinthorsdottir, V., Morris, A.P., Fassbender, A., Rahmioglu, N., De Vivo, I., Buring, J.E., Zhang, F., Edwards, T.L., Jones, S., O, D., Peterse, D., Rexrode, K.M., Ridker, P.M., Schork, A.J., MacGregor, S., Martin, N.G., Becker, C.M., Adachi, S., Yoshihara, K., Enomoto, T., Takahashi, A., Kamatani, Y., Matsuda, K., Kubo, M., Thorleifsson, G., Geirsson, R.T., Thorsteinsdottir, U., Wallace, L.M., i, P.-S.S.I.B.G., Yang, J., Velez Edwards, D.R., Nyegaard, M., Low, S.K., Zondervan, K.T., Missmer, S.A., D'Hooghe, T., Montgomery, G.W., Chasman, D.I., Stefansson, K., Tung, J.Y. and Nyholt, D.R. (2017)
Nature Communications 8 (1) 15539

Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339.
Powell, J.E., Fung, J.N., Shakhbazov, K., Sapkota, Y., Cloonan, N., Hemani, G., Hillman, K.M., Kaufmann, S., Luong, H.T., Bowdler, L., Painter, J.N., Holdsworth-Carson, S.J., Visscher, P.M., Dinger, M.E., Healey, M., Nyholt, D.R., French, J.D., Edwards, S.L., Rogers, P.A. and Montgomery, G.W. (2016)
Hum Mol Genet 25: 5046-5058.

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.
Lu, Y., Cuellar-Partida, G., Painter, J.N., Nyholt, D.R., Australian Ovarian Cancer, S., International Endogene, C., et al., (2015)
Human Molecular Genetics 24: 5955-5964.

Genome-wide association meta-analysis identifies new endometriosis risk loci.
Nyholt, D.R., Low, S.K., Anderson, C.A., Painter, J.N., Uno, S., Morris, A.P., Macgregor, S., Gordon, S.D., Henders, A.K., Martin, N.G., Attia, J., Holliday, E.G., McEvoy, M., Scott, R.J., Kennedy, S.H., Treloar, S.A., Missmer, S.A., Adachi, S., Tanaka, K., Nakamura, Y., Zondervan, K.T., Zembutsu, H. and Montgomery, G.W. (2012).
Nature Genetics 44: 1355-1359.

Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis.
Painter, J.N., Anderson, C.A., Nyholt, D.R., Macgregor, S., Lin, J., Lee, S.H., Lambert, A., Zhao, Z.Z., Roseman, F., Guo, Q., Gordon, S.D., Wallace, L., Henders, A.K., Visscher, P.M., Kraft, P., Martin, N.G., Morris, A.P., Treloar, S.A., Kennedy, S.H., Missmer, S.A., Montgomery, G.W. and Zondervan, K.T. (2011)
Nature Genetics 43: 51-54.

Reproductive Traits and Diseases

Molecular Support for Heterogonesis Resulting in Sesquizygotic Twinning.
Gabbett, M.T., Laporte, J., Sekar, R., Nandini, A., McGrath, P., Sapkota, Y., Jiang, P., Zhang, H., Burgess, T., Montgomery, G.W., Chiu, R. and Fisk, N.M. (2019)
New Eng. J. Med. 380: 842-849.

Identification of nine new susceptibility loci for endometrial cancer.
O'Mara, T.A., Glubb, D.M., Amant, F., Annibali, D., Ashton, K., Attia, J., et al., (2018)
Nat Commun 9: 3166.

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.
Day, F.R., Thompson, D.J., Helgason, H., Chasman, D.I., Finucane, H., Sulem, P., et al., (2017)
Nature Genetics 49: 834-841.

Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility.
Mbarek, H., Steinberg, S., Nyholt, D.R., Gordon, S.D., Miller, M.B., McRae, A.F., Hottenga, J.J., Day, F.R., Willemsen, G., de Geus, E.J., Davies, G.E., Martin, H.C., Penninx, B.W., Jansen, R., McAloney, K., Vink, J.M., Kaprio, J., Plomin, R., Spector, T.D., Magnusson, P.K., Reversade, B., Harris, R.A., Aagaard, K., Kristjansson, R.P., Olafsson, I., Eyjolfsson, G.I., Sigurdardottir, O., Iacono, W.G., Lambalk, C.B., Montgomery, G.W., McGue, M., Ong, K.K., Perry, J.R., Martin, N.G., Stefansson, H., Stefansson, K. and Boomsma, D.I. (2016)
Am J Hun Genet 98: 898-908.

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
Perry, J.R., Day, F., Elks, C.E., Sulem, P., Thompson, D.J., Ferreira, T., et al., (2014)
Nature 514 (7520) 92-97.

Reviews and Commentaries

Should Genetics Now Be Considered the Pre-eminent Etiologic Factor in Endometriosis?
Montgomery, G.W., Mortlock, S. and Giudice, L.C. (2019)
J Minim Invasive Gynecol.

Progesterone Resistance in Endometriosis: an Acquired Property?
McKinnon, B., Mueller, M. and Montgomery, G. (2018)
Trends in Endocrinology and Metabolism 29: 535-548.

Complex genetics of female fertility.
Gajbhiye, R., Fung, J.N. and Montgomery, G.W. (2018)
NPJ Genomic Medicine 3: 29.

Genetics of endometriosis: State of the art on genetic risk factors for endometriosis.
Fung, J.N. and Montgomery, G.W. (2018)
Best Practice and Research Clinical Obstetrics and Gynaecology 50: 61-71.

New Lessons about Endometriosis - Somatic Mutations and Disease Heterogeneity.
Montgomery, G.W. and Giudice, L.C. (2017) New Eng. J. Med. 376: 1881-1882.

Systems Genetics

Genotype-free demultiplexing of pooled single-cell
Xu, J., Falconer, C., Nguyen, Q., Crawford, J., McKinnon, B.D., Mortlock, S., Senabouth, A., Andersen, S., Chiu, H.S., Jiang, L., Palpant, N.J., Yang, J., Mueller, M.D., Hewitt, A.W., Pébay, A., Montgomery, G.W., Powell, J.E. and Coin, L.J.M. (2019)
RNA-seq. Genome Biol 2: 290.

Comprehensive Multiple eQTL Detection and Its Application to GWAS Interpretation.
Zeng, B., Lloyd-Jones, L.R., Montgomery, G.W., Metspalu, A., Esko, T., Franke, L., Vosa, U., Claringbould, A., Brigham, K.L., Quyyumi, A.A., Idaghdour, Y., Yang, J., Visscher, P.M., Powell, J.E. and Gibson, G. (2019)
Genetics vol. 212 no. 3, 905-918

Identification of 55,000 Replicated DNA Methylation
McRae, A.F., Marioni, R.E., Shah, S., Yang, J., Powell, J.E., Harris, S.E., Gibson, J., Henders, A.K., Bowdler, L., Painter, J.N., Murphy, L., Martin, N.G., Starr, J.M., Wray, N.R., Deary, I.J., Visscher, P.M. and Montgomery, G.W. (2018)
QTL. 8: 17605.

Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits.
Wu, Y., Zeng, J., Zhang, F., Zhu, Z., Qi, T., Zheng, Z., Lloyd-Jones, L.R., Marioni, R.E., Martin, N.G., Montgomery, G.W., Deary, I.J., Wray, N.R., Visscher, P.M., McRae, A.F. and Yang, J. (2018)
Nat Commun 9: 918.

Intergenic disease-associated regions are abundant in novel transcripts.
Bartonicek, N., Clark, M.B., Quek, X.C., Torpy, J.R., Pritchard, A.L., Maag, J.L.V., Gloss, B.S., Crawford, J., Taft, R.J., Hayward, N.K., Montgomery, G.W., Mattick, J.S., Mercer, T.R. and Dinger, M.E. (2017)
Genome Biol 18: 241.

The genetic regulation of transcription in human endometrial tissue.
Fung, J.N., Girling, J.E., Lukowski, S.W., Sapkota, Y., Wallace, L., Holdsworth-Carson, S.J., Henders, A.K., Healey, M., Rogers, P.A.W., Powell, J.E. and Montgomery, G.W. (2017) Hum Reprod 32: 893-904.

The Genetic Architecture of Gene Expression in Peripheral Blood.
Lloyd-Jones, L.R., Holloway, A., McRae, A., Yang, J., Small, K., Zhao, J., Zeng, B., Bakshi, A., Metspalu, A., Dermitzakis, M., Gibson, G., Spector, T., Montgomery, G., Esko, T., Visscher, P.M. and Powell, J.E. (2017)
The Genetic Architecture of Gene Expression in Peripheral Blood. 100: 228-237.

Genetic correlations reveal the shared genetic architecture of transcription in human peripheral blood.
Lukowski, S.W., Lloyd-Jones, L.R., Holloway, A., Kirsten, H., Hemani, G., Yang, J., Small, K., Zhao, J., Metspalu, A., Dermitzakis, E.T., Gibson, G., Spector, T.D., Thiery, J., Scholz, M., Montgomery, G.W., Esko, T., Visscher, P.M. and Powell, J.E. (2017)
Nat Commun 8: 483.

Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets.
Zhu, Z., Zhang, F., Hu, H., Bakshi, A., Robinson, M.R., Powell, J.E., Montgomery, G.W., Goddard, M.E., Wray, N.R., Visscher, P.M. and Yang, J. (2016)
Nature Genetics 48: 481-487.

Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations.
Shah, S., Bonder, M.J., Marioni, R.E., Zhu, Z., McRae, A.F., Zhernakova, A., Harris, S.E., Liewald, D., Henders, A.K., Mendelson, M.M., Liu, C., Joehanes, R., Liang, L., Consortium, B., Levy, D., Martin, N.G., Starr, J.M., Wijmenga, C., Wray, N.R., Yang, J., Montgomery, G.W., Franke, L., Deary, I.J. and Visscher, P.M. (2015)
Am J Hun Genet 97: 75-85.

Contribution of genetic variation to transgenerational inheritance of DNA methylation.
McRae, A.F., Powell, J.E., Henders, A.K., Bowdler, L., Hemani, G., Shah, S., Painter, J.N., Martin, N.G., Visscher, P.M. and Montgomery, G.W. (2014)
Genome Biol 15: R73.

Systematic identification of trans eQTLs as putative drivers of known disease associations.
Westra, H.J., Peters, M.J., Esko, T., Yaghootkar, H., Schurmann, C., Kettunen, J., Christiansen, M.W., Fairfax, B.P., Schramm, K., Powell, J.E., Zhernakova, A., Zhernakova, D.V., Veldink, J.H., Van den Berg, L.H., Karjalainen, J., Withoff, S., Uitterlinden, A.G., Hofman, A., Rivadeneira, F., t Hoen, P.A., Reinmaa, E., Fischer, K., Nelis, M., Milani, L., Melzer, D., Ferrucci, L., Singleton, A.B., Hernandez, D.G., Nalls, M.A., Homuth, G., Nauck, M., Radke, D., Volker, U., Perola, M., Salomaa, V., Brody, J., Suchy-Dicey, A., Gharib, S.A., Enquobahrie, D.A., Lumley, T., Montgomery, G.W., Makino, S., Prokisch, H., Herder, C., Roden, M., Grallert, H., Meitinger, T., Strauch, K., Li, Y., Jansen, R.C., Visscher, P.M., Knight, J.C., Psaty, B.M., Ripatti, S., Teumer, A., Frayling, T.M., Metspalu, A., van Meurs, J.B. and Franke, L. (2013)
Nature Genetics 45: 1238-1243.

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Professor Montgomery has made substantial contributions to the worldwide effort to map genomic regions contributing to risk for complex traits and diseases, including endometriosis, age at menarche and menopause, cancers of the reproductive tract, melanoma and inflammatory bowel disease. He is conducting systems genetics and functional studies to identify the genes and pathways affected by these genetic risk factors

  • Professor Peter Rogers, Professor of Women’s Health Research, Department of Obstetrics and Gynaecology, University of Melbourne
  • Professor Nick Martin, QIMR Berghofer Medical Research Institute
  • International Endometriosis Genetics Consortium
  • Consortium on Epigenetic Control of Gene Expression on Endometrium
  • ReproGen Consortium, an international network of investigators interested in better understanding the genetic basis of reproductive ageing
  • GenoMEL, the international consortium on the genetics of melanoma
  • QENDO (Endometriosis Association Qld Inc.)

Our Team

  Group Leader