Genetic Physiology

Introduction

Welcome to the Home page of the Genetic Physiology Group. This page introduces the current research team and research topics of our group, with relevant links to publications, current grants and collaborators. The research interests of our group are varied, but tied to a common theme that of understanding the genetics behind common complex diseases and phenotypes. These include cardiovascular disease and its risk factors, adult height, and androgenetic alopecia (common baldness). Our team of research fellows, biostatisticians, postgraduate research students and research assistants are employing the latest research methods, laboratory equipment and novel statistical methods to define DNA variation that contribute to cardiovascular risk, height and baldness.

Contents

• Lab Members
• Special Collaborators
• Overview of The Victorian Family Heart Study
• News/Conferences
• Research Projects
• Facilities and Experimental Techniques
• Collaborators
• Recent Grants
• Selected Publications

Lab Members

Special Collaborators

*Murdoch Childrens Research Institute (MCRI)
**Centre for Molecular, Environmental, Genetic and Analytic Epidemiology (MEGA)

Overview of The Victorian Family Heart Study (VFHS) by Prof. Stephen Harrap

In 1990 we established the Victorian Family Heart Study (VFHS) and after 6 years we successfully recruited approximately 3000 healthy adults who comprised about 800 families (each of mum, dad and at least 1 natural offspring). These families were enriched by the inclusion of families with twins. For this we are indebted to Professor John Hopper and the Australian Twin Registry. The result is a unique resource for studying the genetic and environmental factors that determine simple traits such as blood pressure, heart rate, weight, height, cholesterol, baldness and fibrinogen. To do so we have taken advantage of the most modern technology and brought together a team with skills in molecular biology and genetic biostatistics. The VFHS is renown internationally for its discoveries in relation to blood pressure and the Y chromosome, baldness and the androgen receptor gene, the genetics of height and ongoing studies of cardiovascular risk factors.

To complement the VFHS focus on risk factors, we established the Acute Myocardial Infarction Genetic Origins (AMIGO) Study looking at the genetics of heart attack (acute coronary syndrome). This was one of the first studies in the world to report genome wide linkage for this condition that remains the single most common cause of death. Although a relatively small study, the care with which it was undertaken maximised the outcomes and our results have been corroborated by subsequent meta-analyses. We are now moving ahead to identify the particular genes and variations in DNA that are responsible. To understand the genetic basis of heart size (which after age is the single most important cardiovascular risk factor), I initiated series of breeding studies in rats in 1989. This resulted in the first identification by genome wide scanning of a gene that controls heart size independent of blood pressure. Our more recent studies with Dr Robert DiNicolantonio are homing in on the precise gene and mutation that explain this action.

The breeding continued down a parallel track to produce a new strain of rat that has normal blood pressure but a big heart. These Hypertrophic Heart Rats (HHR) have very greatly enlarged heart muscle cells and the challenge now is to understand the exact developmental and physiological mechanism. The funding for the family and breeding studies has been generously provided from a variety of sources including the National Health and Medical Research Council, the Victorian Health Promotion Foundation, the Australian Research Council, the National Heart Foundation, the Cabrini Medical Education & Research Foundation and the Clive & Vera Ramaciotti Foundation.

News/Conferences

• The members of the laboratory enjoyed both the professional and social aspects of the 30th Anniversary Annual Scientific meeting of the High Blood Pressure Research Council of Australia held in Melbourne in December 2008.

• Justine and Joanna went to the 58th American Society of Human Genetics meeting in Philadelphia, November 2008.

Research Projects

Understanding the allelic architecture of adult height

Adult height is widely regarded as the human phenotype must amenable to genetic dissection. It is easily and accurately measurable, and has a strong heritable component. We have performed candidate gene association studies and genome-wide scans using carefully phenotyped participants of the Victorian Family Heart Study to locate regions of the genome likely to contain genes controlling final adult height. We are currently funded by the ARC to analyse these regions for DNA variants that contribute to differences in stature, and to develop and use new statistical techniques (in collaboration with Professor John Hopper, Centre for MEGA Epidemiology at the University of Melbourne) to uncover the involvement of these variants in men and women. The involvement of these genes during pubertal growth will also be examined in collaboration with Professor George Patton, Centre for Adolescent Health, University of Melbourne). Our findings to date include the association of the Y chromosome and the aromatase gene (CYP19) with adult height¹, and our genome-wide scan has suggested a height determining gene on Chromosome 3, in a region containing a number of interesting candidate genes.

The genetics of androgenetic alopecia

Androgenetic alopecia (AGA), often referred to as pattern or common baldness, is a condition that requires genetic predisposition and the presence of androgens. It occurs in men and women, although it is unclear as to whether male and female AGA are identical conditions. The genetic basis of AGA remains largely unknown. We have performed a number of case-control genetic association studies using participants of the VFHS, concentrating thus far on candidate genes related to the sex steroid pathways. Our group was the first in the world to demonstrate the association of the first gene, the androgen receptor (AR), with common male baldness², a finding that was recently replicated by other international investigators. We are continuing to define this association, and track down the exact DNA variants in this gene that contribute to hair loss in men. We are also investigating the role of this gene and others in common female balding in collaboration with Professor Rodney Sinclair, University of Melbourne Department of Dermatology, St Vincent’s Hospital.

Sex-dependency of cardiovascular risk factors and the role of sex steroid genes

Men are more susceptible to cardiovascular disease than women, and many of the traditional risk factors, such as blood pressure and cholesterol levels are less favourable in men. The broad aim of this project is to elucidate the genetic component of this sex dependency, and to develop novel statistical approaches to enable identification of DNA variants that affect cardiovascular risk factors to different extents between the sexes. We have examined several sex steroid related candidate genes for their role in cardiovascular risk determination and are following up some interesting results. Our published findings related to this project include the association of the Y chromosome with blood pressure³ – previously reported in rats, and since replicated by other research groups, and the sex-dependent association of the estrogen receptor genes, ERa and ERb, with blood pressure⁴.

Facilities and Experimental Techniques

Primarily, our laboratory uses SNP genotyping, mutation scanning and sequencing techniques to investigate our complex human traits of interest. We are set up to process DNA using our two platforms- the Light Scanner (Fig 1) and the MegaBace 1000 (Fig 2). The Light Scanner technology is based on high resolution melting, and provides us with higher throughput capabilities. The MegaBace 1000 DNA analysis platform is a capillary based system and allows us to sequence DNA in-house.

Fig 1: Sophie hard at work on the MegaBace 1000.	Fig 2: Joanna completing a run on the Light Scanner.

With our collaborators, members of our laboratory group have recently begun studies in a variety of areas. We are using pronuclear injections into mouse embryos to generate transgenic embryos for screening gene regulators, dissecting human hair follicles for DNA methylation analysis, performing high throughput SNP genotyping using a Sequenom platform, and looking at copy number variation using a multiplex ligation-dependent probe assay.

Collaborators

• Professor John Hopper, Dr Lyle Gurrin, Dr Graham Byrnes (MEGA Epidemiology). Statistical methods and applications.
• The Second Australian National Blood Pressure Study.
• Professor Tien Wong, Associate Professor Paul Baird (Centre for Eye Research Australia).
• Dr Stephen Hunt (University of Utah).
• Professor John Bateman, Dr Richard Saffrey, Dr Jeff Craig, Dr Nick Wong (Murdoch Childrens Research Institute).
• Dr Stefan White (MCRI). Examining copy number variation around the AR gene.
• Dr Les Jones (CSIRO). Investigating methylation differences around the AR gene in tissues from different locations in human scalp.
• Professor Sam Berkovic (The University of Melbourne, Department of Medicine, Austin Health and Northern Health).
• Professor Colin Nichols (University of Washington in St Louis).
• Professor Vernon Oh (National University of Singapore).
• Professor Rodney Sinclair (Department of Dermatology, St.Vincent’s Hospital).
• Professor Graham Watt (Department of General Practice, Glasgow).
• Associate Professor Jenny Wilkinson-Berka (Monash University).
• Associate Professor Diane Fatkin (Victor Chang Cardiac Research Institute). Genetic and environmental influences on atrial fibrillation.
• Australian Medical Bioinformatics Resource (AMBeR).
• Profs John Chalmers, Stephen Macmahon, Bruce Neal (George Institute for International Health, Sydney)
• Prof Christophe Tzourio (INSERM U708, Paris)
• Prof Leeanne Grigg (Cardiology Department, Royal Melbourne Hospital)
• Prof Gavin Becker (Nephrology Department, Royal Melbourne Hospital)
• Prof Xavier Jeunemaître (Collège de France, Paris)

Recent Grants

Selected Publications

2009

Joanna Cobb, Stefan White, Stephen Harrap, Justine Ellis. (2009) "Androgen Receptor Copy Number Variation and Androgenetic Alopecia: A Case-Control Study" PLoS ONE 4(4): e5081. doi:10.1371/journal.pone.0005081

Du X, Ninomiya T, de Galan B, Abadir E, Chalmers J, Pillai A, Woodward M, Mark Cooper M, Harrap S, Hamet P, Poulter N, Lip GYH, Patel A. (2009) "Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation ­ results of the ADVANCE study" Eur Heart J (accepted 22 Jan 09)

Yip L, Zaloumis S, Irwin D, Severi G, Hopper J, Giles G, Harrap S, Sinclair R, Ellis J. (2009) "Gene-wide association study of the aromatase gene (CYP19A1) with female pattern hair loss" Br J Dermatol. (accepted 31 Jan 09)

Porrello ER, D¹Amore A, Curl CL, Allen AM, Harrap SB, Thomas WG, Delbridge LMD. (2009) "Cardiomyocyte autophagy is mediated by the angiotensin II type 1 receptor and antagonized by the type 2 receptor" Hypertension (accepted 24 Feb 09)

Porrello ER, Bell JR, Schertzer JD, Curl CL, McMullen JR, Mellor KM, Ritchie RH, Lynch GS, Harrap SB, Thomas WG, Delbridge LMD. (2009) "Heritable pathologic cardiac hypertrophy in adulthood is preceded by neonatal cardiac growth restriction" Am J Physiol. (accepted 2 Dec 2008)

2008

Cobb J, Büsst CJ, Petrou S, Harrap S, Ellis J. (2008) "Searching for functional genetic variants in non-coding DNA" Clin Exp Pharmacol Physiol. 35:372-375

Tzourio C, Arima H, Harrap S, Anderson C, Godin O, Woodward M, Neal B, Bousser MG, Chalmers J, Cambien F, MacMahon S. (2008) "APOE genotype, ethnicity, and the risk of cerebral hemorrhage" Neurology 70:1322-1328

Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu LS, Mancia G, Mogensen CE, Pan CY, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. (2008) "Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes" New England Journal of Medicine 24:2560-2572

Dwyer JP, Rotchie ME, Smyth GK, Harrap SB, Delbridge LM, Domenighetti AA, Di Nicolantonio R. (2008) "Myocardial gene expression associated with genetic cardiac hypertrophy in the absence of hypertension" Hypertens Res. 31:941-955

Bell J, Porello E, Huggins K, Harrap SB, Delbridge LM. (2008) "The intrinsic resistance of female hearts to an ischemic insult is abrogated in primary cardiac hypertrophy" Am J Physiol. 294:H1514-H1522

Zentner D, du Plessis M, Brenneke S, Wong J, Grigg L, Harrap S. (2008) "Deterioration in cardiac systolic and diastolic function late in normal human pregnancy" Clin Sci. 116:599-606

Scurrah KJ, Zaloumis SG, Hopper JL, Harrap SB. (2008) "Contribution of genes and environment to varIation in postural changes in mean arterial and pulse pressure" J Hypertens. 26:2319-2325

2007

Chen CY, Stankovich J, Scurrah KJ, Garoufalis P, Dirani M, Pertile KK, Richardson AJ, Baird, PN (2007) "Linkage Replication of the MYP12 locus in common myopia" Investigative Ophthalmology and Visual Science 48:4433-4439

Büsst CJ, Scurrah KJ, Ellis JA, Harrap SB (2007) "Selective genotyping reveals association between the epithelial sodium channel g-subunit and systolic blood pressure: The Victorian Family Heart Study" Hypertension 50:672-678

Chen CY, Scurrah KJ, Stankovich J, Garoufalis P, Dirani M, Pertile KK, Richardson AJ, Baird, PN (2007) “Heritability and shared environment estimates for myopia and associated ocular biometric traits: The Genes in Myopia Family Study” Human Genetics 121:511-520

Ellis JA, Scurrah KJ, Cobb JE, Zaloumis SG, Duncan AE, Harrap SB. (2007) “Baldness and the Androgen Receptor - The AR polyglycine repeat polymorphism does not confer susceptibility to androgenetic alopecia” Human Genetics 121:451-457

Ellis J, Scurrah K, Duncan A, Lamantia A, Byrnes G, Harrap S. (2007) “Comprehensive multi-stage linkage analyses identify a locus for adult height on chromosome 3p in a healthy Caucasian population” Human Genetics 121:213-222

Harrap SB. (2007) "Cardiovascular genetics ­ Two steps forward, one step back" Ann Acad Med Singap 36:373-5

Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S, Poulter N, Marre M, Cooper M, Glasziou P, Grobbee DE, Hamet P, Heller S, Liu LS, Mancia G, Mogensen CE, Pan CY, Rodgers A, Williams B. (2007) "Effects of fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised control trial" Lancet 370:829-840

2006

Scurrah KJ, Byrnes GB, Hopper JL, Harrap SB. (2006) “Sex differences in genetic and environmental determinants of pulse pressure” Genetic Epidemiology 30:397-408

Harrap SB, Wong Z, Scurrah KJ, Lamantia A. (2006) “Genome-wide linkage analysis of population variation in high density lipoprotein cholesterol” Human Genetics 199:541-546

2005

Scurrah,K., Wong,Z., Ellis,J., Hopper,J. and Harrap,S. (2005) Familial analyses of pulse pressure: extensions to standard variance components models. IWSM2005 conference proceedings.

The BHF Family Heart Study Research Group (2005) “A genome-wide linkage study of 1933 families affected by premature coronary artery disease: The British Heart Foundation Family Heart Study” American Journal of Human Genetics 77:1011-1020

Gurrin, L.C., Scurrah, K.J., and Hazelton,M.L. (2005) “Tutorial in biostatistics: spline smoothing with linear mixed models” Statistics in Medicine 24: 3361-3381

Burton, P.R., Scurrah, K.J., Tobin, M.D., Palmer, L.J. (2005). “Covariance components models for longitudinal familial data.” International Journal of Epidemiology 34:1063-1077

Tobin, M.D., Sheehan, N.A., Scurrah, K.J., Burton, P.R. (2005) “Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure.” Statistics in Medicine 24:2911-2935

Andrew, T., Antoniades, L., Scurrah K.J., MacGregor, A.J., Spector, T.D. (2005) “The risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing bone mineral density” Journal of Bone and Mineral Research 20:67-74

Scurrah K.J., Gurrin L.C., Palmer L.J., Burton P.R. (2005) “The estimation of genetic and environmental factors for binary traits using family data.” Statistics in Medicine 24:1613-1618

2004

Harrap,S.B., Cui,J.S., Wong,Z.Y.H. and Hopper,J.L. (2004) Familial and genomic analyses of postural changes in systolic and diastolic blood pressure. Hypertension, 43(3):586-591

⁴JA Ellis, T Infantino, SB Harrap: Sex dependent association of blood pressure with oestrogen receptor genes ERa and ERb. Journal of Hypertension 2004; 22:1127-1131

2003

JA Ellis, SB Harrap: Invited Commentary: Tall stories: the devilish detail of genetic association studies. Clinical Endocrinology 2003; 59:278-279

Scurrah, KJ, Tobin, MD, Burton, PR. (2003) “Longitudinal variance components models for systolic blood pressure, fitted using Gibbs sampling.” BioMed Central Genetics 4 (Suppl 1): Article # S25

Gauderman, W.J., Macgregor, S., Briollais, L., Scurrah, K.J., Tobin, M.D., Park, T., Wang, D., Rao, S., John, S., Bull, S. (2003) “Longitudinal data analysis in pedigree studies.” Genetic Epidemiology 25 (Suppl 1):S18-S28

2002

Harrap,S.B., Wong,Z.Y.H., Stebbing,M., Lamantia,A. and Bahlo,M. (2002) Blood pressure QTLs identified by genome-wide linkage analysis and dependence on associated phenotypes. Physiological Genomics 8:99-105

Harrap,S.B., Zammit,K.S., Wong,Z.Y.H., Williams,F.M., Bahlo,M., Tonkin,A.M. and Anderson,S.T. (2002) Genome-wide linkage analysis of the acute coronary syndrome suggests a locus on chromosome 2. Arteriosclerosis, Thrombosis, and Vascular Biology 22:874-878

JA Ellis, R Sinclair, SB Harrap: Androgenetic alopecia: pathogenesis and potential for therapy. Expert Reviews in Molecular Medicine 19 November 2002; http://www.expertreviews.org/02005112h.htm

2001

Ellis,J.A., Wong,Z.Y.H., Stebbing,M. and Harrap,S.B. (2001) Sex genes and blood pressure. Clin. Exp. Pharmacol. Physiol. 28:1053-1055

¹JA Ellis, M Stebbing, SB Harrap: Significant population variation in adult male height associated with the Y chromosome and the aromatase gene. Journal of Clinical Endocrinology and Metabolism 2001; 86:4147-4150

JA Ellis, M Stebbing, SB Harrap: Male pattern baldness is not associated with established cardiovascular risk factors in the general population. Clinical Science 2001; 100:401-404

²JA Ellis, M Stebbing, SB Harrap: Polymorphism of the androgen receptor gene is associated with male pattern baldness. Journal of Investigative Dermatology 2001; 116:452-455

J Ellis, SB Harrap: The genetics of androgenetic alopecia. Clinics in Dermatology 2001; 19:149-154

Scurrah, K.J., Sheehan, N.A., Burton, P.R. (2001). “Association and linkage for age at onset of a common oligogenic disease using genetic variance component models.” Genetic Epidemiology 21 (Suppl 1):S680-S685