Molecular Epidemiology
Staff
Funding
Collaborators
Key Publications
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Lab Head: Dr Grant Montgomery
The Molecular Epidemiology Group investigates the pattern of disease in families using high throughput genomic platforms for DNA analysis. The group combines research on major projects (the genetics of Endometriosis, DZ Twinning, Melanoma, Alcohol and Drug Dependence) and provision of genotyping services (zygosity testing, microsatellite and SNP genotyping), sample processing and management of the extensive collection of samples held by the Genetic Epidemiology and Molecular Epidemiology Laboratories.
Endometriosis
(Grant Montgomery, Sue Treloar, Zhen Zhen Zhao, Jodie Painter, Lien Le, Shane Thomas, Leanne Wallace)
Endometriosis is a common gynaecological disease that affects up to 10% of women in their reproductive years. It causes pelvic pain, severe dysmenorrhea, and sub-fertility. The disease is defined as the presence of tissue resembling endometrium in sites outside the uterus. Its cause remains uncertain despite >50 years of hypothesis-driven research, and thus the therapeutic options are limited. Disease predisposition is inherited as a complex genetic trait, which provides an alternative route to understanding the disease.
Our aim is to identify genes that influence women's susceptibility to endometriosis and understand pathways to disease. In collaboration with Dr Sue Treloar and Prof Nick Martin, we have identified susceptibility loci, using a positional cloning approach. We conducted a linkage study of 1,176 families, each with at least two members-mainly affected sister pairs-with surgically diagnosed disease. We have identified a region of significant linkage on chromosome 10q26 (see figure below). We are conducting fine mapping studies across this chromosomal region to identify positional genetic variants that influence the risk of developing this debilitating disease. In addition, we've conducted separate studies on the 3 most promising candidate genes within the linkage region, but found no association between these genes and the susceptibility to endometriosis.
Significant recent technological and bioinformatic advances have paved the way for a new era in genetic research - genome-wide association (GWA), where 1000s of samples can be efficiently genotyped and analysed at up to (currently) 1 million DNA markers at a time. To take advantage of this new methodology and futher the investigation of genetic causes underlying the susceptibility to endometriosis, we recently formed the International Endogene Consortium in collaboration with researchers from the UK (Dr Krina Zondervan and Professor Stephen Kennedy, University of Oxford) and the USA (Dr Stacey Missmer, Harvard School of Public Health). Funded by the Wellcome Trust (UK), in 2008 the International Endogene Consortium will genotype approximately 3000 endometriosis cases (2000 from Australia) at >600,000 genetic markers, comparing these to 6000 Wellcome Trust control samples in the largest case:control genetic association study for endometriosis to date.
Dizygotic Twins
(Grant Montgomery, Zhen Zhen Zhao, Jodie Painter, Anjali Henders, Shane Thomas, Lien Le, Anthony Caracella)
Why do twins run in some families? The tendency to conceive spontaneous dizygotic twins is a complex trait influenced by genetic and environmental factors with contributions from family history and maternal age. Finding the gene(s) responsible for twinning is likely to provide fundamental insights into mechanisms of female fertility and may have practical implications for controlling fertility and infertility. We have expanded our study to recruit one thousand pairs of sisters from Australia and the Netherlands to complete a genome scan and subsequent fine mapping of candidate regions in these families.
A novel finding from our work was the discovery of a loss of function mutation in the oocyte specific growth factor (GDF9) in two sisters with twins. The mutation was not found in a further 429 families. We have tested the role of common variation in this gene by genotyping eight single nucleotide polymorphisms (SNPs) across the GDF9 locus in 605 families with dizygotic twins. We found no evidence for association between common variants and twinning in our families.
Genetic Epidemiology Studies
The laboratory supports a range of studies in Genetic Epidemiology by processing blood samples and extracting DNA. We maintain a large biobank of samples, prepare and dispatch samples for genome scans at a variety of sites and conduct SNP genotyping on our Sequenom MassARRAY genomics platform and Illumina BeadStation. We conduct ABI Profiler microsatellite marker analysis on an ABI 3100 to confirm the zygosity of twins for a range of studies.
Some examples of these studies include collaborative projects such as the genetics of Melanoma, Pigmentation and Inflammatory Bowel Disease. Publications arising from this work can be found below.
Staff
| Labhead: | Dr Grant Montgomery |
| Research Officers: | Dr Zhen Zhen Zhao Dr Penelope Lind Dr Jodie Painter |
| Laboratory Coordinators: | Anjali Henders Megan Campbell |
| Bioinformatician: | Lien Le |
| Research Assistants: | Kalpana Patel Anthony Caracella Leanne Wallace Lisa Bardsley Shane Thomas Steve Crooks Sara Smith Melinda Richter |
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Funding
We gratefully acknowledge support from the following organisations and funding bodies:
- NHMRC (National Health and Medical Research Council)
- NIH (National Cancer Institute - USA)
- NIH (National Institute of Child Health and Human Development - USA)
- NIH (National Institute of Alcoholism and Alcohol Abuse - USA)
- NIH (National Institute of Drug Abuse - USA)
- Wellcome Trust (UK)
Collaborators
The Molecular Epidemiology laboratory works closely in collaborations within QIMR- Professor Nick Martin and other senior researchers within the Genetic Epidemiology laboratory
- Professor Peter Visscher of the Queensland Statistical Genetics laboratory
- Dr Nick Hayward of the Oncogenomic laboratory
- Dr Graham Radford-Smith of the Inflammatory Bowel Disease laboratory of the RBH Research Foundation.
Dr Montgomery also has external collaborations with:
- Professor Stephen Kennedy, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, UK
- Professor Dorret Boomsma, Netherlands Twin Registry, Department of Biological Psychology, Free University, Amsterdam, Netherlands
- Associate Professor Peter Rogers, Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
- Dr John Whitfield, Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney
- Professor Andrew Heath, Department of Psychiatry, Washington University Medical School, St Louis, USA
- Professor Richard Todd, Department of Psychiatry, Washington University Medical School, St Louis, USA
- Dr Elliot Nelson, Department of Psychiatry, Washington University Medical School, St Louis, USA
Key Publications
Hoekstra C, Zhao ZZ, Lambalk CB, Willemsen G, Martin NG, Boomsma DI and Montgomery GW (2008) Dizygotic twinning. Hum Reprod Update 14: 37-47.
Macgregor S, Zhao ZZ, Henders AK, Martin NG, Montgomery GW and Visscher PM (2008) Highly cost-efficient genome-wide association studies using DNA pools and dense SNP arrays. Nuc Acids Res 36: e35.
Sturm RA, Duffy DL, Zhao ZZ, Leite FPN, Stark MS, Hayward NK, Martin NG and Montgomery GW (2008) A single SNP in an evolutionarily conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color. Am J Hum Genet 80: 241-252.
Zhao ZZ, Pollock PM, Thomas S, Treloar SA, Nyholt DR and Montgomery GW (2008) Common variation in fibroblast growth factor receptor 2 coding region is not associated with endometriosis risk. Hum Reprod.
Duffy DL, Montgomery GW, Chen W, Zhao ZZ, Le L, James MR, Hayward NK, Martin NG and Sturm RA (2007) A three-SNP haplotype in the first intron of OCA2 explains most human eye color variation. Am J Hum Genet 80: 241-252.
Saccone SF, Pergadia ML, Loukola A, Broms U, Montgomery GW, Wang JC, Agrawal A, Dick DM, Heath AC, Todorov AA et al. (2007) Genetic Linkage to Chromosome 22q12 for a Heavy Smoking Quantitative Trait in Two Independent Samples. Am J Hum Genet 80,856-866.
Souter VL, Parisi MA, Nyholt DR, Kapur RA, Henders AK, Opheim KE, Gunther DF, Mitchell ME, Glass IA and Montgomery GW (2007) A Case of True Hermaphroditism Reveals an Unusual Mechanism of Twinning. Human Genet 121: 179-185.
Zhao ZZ, Nyholt DR, Le L, Thomas S, Engwerda C, Randall L, Treloar SA and Montgomery GW (2007) Genetic variation in tumour necrosis factor and lymphotoxin is not associated with endometriosis in an Australian sample. Hum Reprod 22: 2389-2397.
Zondervan KT, Treloar SA, Lin J, Weeks DE, Nyholt DR, Mangion J, MacKay IJ, Cardon L, Martin NG, Kennedy SH et al. (2007) Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian autosomal inheritance on chromosome 7p13-15. Hum Reprod 22: 717-728.
Macgregor S, Visscher PM and Montgomery GW (2006) Analysis of pooled DNA samples on high density arrays without prior knowledge of differential hybridization rates. Nucleic Acids Res 34: e55.
Montgomery GW, Zhu G, Hottenga JJ, Duffy DL, Heath AC, Boomsma DI, Martin NG and Visscher PM (2006) HLA and genome wide allele sharing in DZ twins. Am J Hum Genet 79: 1052-1058.
Palmer JS, Zhao ZZ, Hoekstra C, Hayward NK, Webb PM, Whiteman DC, Martin NG, Boomsma DI, Duffy DL and Montgomery GW (2006) Novel variants in growth differentiation factor 9 in mothers of twins. J Clin Endo Metab 91: 4713-4716.
Treloar SA, Zhao ZZ, Le L, Zondervan KT, Martin NG, Kennedy S, Nyholt DR and Montgomery GW (2007) Variants in EMX2 and PTEN do not contribute to risk of endometriosis. Mol Hum Reprod 13: 587-594.
Dickson, PA, Montgomery, GW, Henders, A, Campbell, MJ, Martin, NG and James, MR. (2005) Evaluation of multiple displacement amplification in a 5 cM STR genome-wide scan. Nucleic Acids Research 33: e119
Nyholt, DR, Morley, KI, Medland, SE, Ferreira, MAR, Boomsma, DI, Heath, AC, Merikangas, KR, Montgomery, GW and Martin, NG. (2005) Genomewide Significant Linkage to Latent Class Analysis Derived Migrainous Headache on Chromosome 5q21. American Journal of Human Genetics 77: 500-512
Posthuma, D, Luciano, M, Geus, EJ, Wright, MJ, Slagboom, PE, Montgomery, GW, Boomsma, DI and Martin, NG. (2005) A genomewide scan for intelligence identifies quantitative trait loci on 2q and 6p. American Journal of Human Genetics 77: 318-326
Treloar SA, Wicks J, Nyholt DR, Montgomery GW, Bahlo M, Smith V, Dawson G, Mackay IJ, Weeks DE, Bennett ST, Carey A, Ewen-White KR, Duffy DL, O'Connor DT, Barlow DH, Martin NG, Kennedy SH. (2005) Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26. American Journal of Human Genetics 77: 365-76
Treloar SA, Zhao, ZZ, Armitage T, Duffy DL, Wicks J, O'Connor DT, Martin NG, Montgomery GW. (2005) Association between polymorphisms in the progesterone receptor gene and endometriosis. Molecular Human Reproduction 11: 641-647.
Zhao, ZZ, Nyholt, DR, James, MR, Mayne, R, Treloar, SA and Montgomery, GW. (2005) A comparison of DNA pools constructed following whole genome amplification for two-stage SNP genotyping designs. Twin Research and Human Genetics 8: 353-361
Montgomery, G. W., Zhao, Z. Z., Marsh, A. J., Mayne, R., Treloar, S. A., James, M. R., Martin, N. G., Boomsma, D. L., and Duffy, D. L. (2004). A deletion mutation in GDF9 in sisters with spontaneous DZ twins. Twin Research 7: 548-555.
Souter V, Kapur RP, Nyholt DR, Skogerboe K, Myerson D, Ton C, Easterling T, Shields L, Montgomery GW, and Glass IA. (2003) A report of dizygous monchorionic twins. New England Journal of Medicine 349: 152-156
Montgomery GW, Duffy DL, Hall J, Kudo M, Martin NG, and Hsueh AJ. (2001) Mutations in exon 10 of the follicle-stimulating hormone receptor are not a common cause of familial dizygotic twinning. The Lancet 357: 773-774
Galloway SM, McNatty KP, Cambridge LM, Laitinen MPE, Juengel JL, Jokiranta S, McLaren RJ, Luiro K, Dodds KG, Montgomery GW, Beattie AE, Davis GH, and Ritvos O. (2000) Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nature Genetics 25: 279-283
Montgomery GW, Crawford AM, Penty JM, Dodds KG, Ede AJ, Henry HM, Pierson CA, Lord EA, Galloway SM, Schmack AE, Sise JA, Swarbrick PA, Hanrahan V, Buchanan FC, and Hill DF. (1993) The ovine Booroola fecundity gene (FecB) is linked to markers from a region of human chromosome 4q. Nature Genetics 4: 410-414