Genetic Epidemiology

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Lab Head: Professor Nick Martin
Nick.Martin@qimr.edu.au

The Genetic Epidemiology Group under Professor Nick Martin investigates the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems. The Genetic Epidemiology group also has its own webserver at genepi.qimr.edu.au.

One focus is the way melanoma runs in families. All familial cases and twins with melanoma diagnosed in Queensland and NSW from 1982-1990 have been identified. By obtaining detailed information on sun exposure, natural coloration and moliness in index cases and their relatives, a much better perspective of the role of genetic factors in melanoma is being gained. It is clear that moles (melanocytic naevi) are a major risk factor for melanoma. It is therefore important that we know more about the factors responsible for development and change of moles. In an NHMRC/QCF-funded study, we are counting and mapping moles in over 600 pairs of Brisbane 12 year old twins and following them up at their fourteenth birthday. We have shown that individual differences in moliness in this sample are largely genetic and that much of this variation occurs at the familial melanoma locus on chromosome 9.

Alcohol consumption is associated with many medical and social variables. With support from both NHMRC and three large grants from the U.S. National Institute of Alcoholism and Alcohol Abuse, 5,000 pairs of twins plus their relatives - 23,000 subjects in all - have been surveyed, and we have conducted telephone interviews with over 11,000 twins and 4000 of their spouses. Genetic factors account for about two thirds of the susceptibility to alcoholism in both women and men in Australia. Now we are obtaining blood samples from these twins with a view to identifying particular genes predisposing to drinking problems. A major finding this past year is that the alcohol dehydrogenase gene complex on chromosome 4 has a significant effect on risk of alcoholism.

The new challenge in genetic epidemiology, made possible by recent advances in molecular biology and advances in automation and robotics, is to identify the particular genes involved in complex disease etiology. QIMR is a major partner in the CRC for Discovery of Genes for Common Human Diseases. The key resource for such advances to be possible is a large sample of pairs of relatives measured for the traits of interest. Studies conducted by QIMR of more than 7,000 twin pairs over the past ten years provide just such a resource.

We are embarking on projects to find major genes influencing several important women's health problems including endometriosis, the latter being a major risk factor for infertility. We are also interested in the genetics of super-fertility, as manifested in familial dizygotic twinning and have genotyped 213 pairs of sisters who each have DZ twins in order to find the genes responsible.

Genetics of alcohol and nicotine dependence
(N.G. Martin, D. Statham, in collaboration with A.C. Heath and P.A.F. Madden, Washington University School of Medicine, St Louis and W. Slutske, University of Missouri)
The genetic epidemiology group is at the forefront of work on the genetics of alcoholism and, from questionnaire and interview studies involving 6000 twins over the past 19 years, we have estimated that in Australia 64% of variance in liability to alcoholism is genetic in both men and women. We are also interviewing offspring aged 14-28 of twins with a view to disentangling the complex relationship of conduct disorder and alcohol dependence. New NIH grants will enable us to search for major genes influencing risk of alcoholism and smoking addiction.

A twin study of mole development in adolescence
(N.G. Martin, A.C. Green, N.K. Hayward, D. Duffy, A. Eldridge, M. Grace, G. Zhu)
It is clear that moles are a major risk factor for melanoma. Over the past nine years we have counted and mapped moles in over 600 pairs of Brisbane 12 year old twins and have followed up more half of them so far at age 14; we have also examined over 150 of their siblings. Analysis suggests very substantial genetic determination of mole count (>90%) and a major role for the familial melanoma gene CDKN2A in the etiology of flat moles, but not of raised ones. We are in the process of linkage disequilibrium mapping in the p16 gene region on chromosome 9p to try and identify the genes responsible.

A twin study of mental abilities and cognitive performance
(N.G. Martin, M. Wright, A. Eldridge, M. Grace, N. Hansel, M. Luciano, in collaboration with Profs. G & L Geffen and Dr. G. Smith, University of Queensland)
The same twins taking part in the mole study return at age 16 to take part in MAPS, the Mental Abilities and Performance Study. Twins are tested for complex reaction time, inspection time, working memory and evoked potentials are recorded. The aim is to estimate the extent to which these measurements are genetically influenced, and, eventually, to use linkage analysis to locate the major genes. So far over 400 pairs and a substantial number of siblings have been tested. The role of triplet repeat expansions of normal cognitive functioning is being investigated.

A twin study of blood cell numbers
(D.M. Evans, N.G. Martin, in collaboration with Prof. I. Frazer, University of Queensland)
The same twins taking part in the mole and MAPS studies at ages 12, 14 and 16 donate a small blood sample at each visit and this is analysed in a Coulter counter to obtain counts of various blood cell types. Lymphocytes are also typed with markers CD3, CD4, CD8, CD19 and CD56. Analysis of data from nearly 400 pairs at age 12 reveals that most of these haematological measures are strongly inherited, at least 80% of variance being genetic. We are studying the longitudinal development of these cell numbers and using sib-pair linkage analysis to find genes of major influence on them.

Biology and molecular genetics of dizygotic twinning
(G.W. Montgomery, N.G. Martin, D.L. Duffy, A. Henders)
It is common knowledge that DZ twins tend to run in families but the endocrinology and mode of inheritance is not understood. In genetic studies, we have ascertained 213 pairs of sisters each of whom has had spontaneous DZ twins. A genome scan is complete and 330 markers have been typed. Several suggestive linkages have been found and are being pursued with extra markers and extra families. It is expected that such genes will yield major insights into the regulation of female fertility.

The role of ADH and ALDH polymorphism in alcohol sensitivity in humans
(N.G. Martin, A.J. Birley and J.B. Whitfield, Royal Prince Alfred Hospital, Sydney)
In 1979-81 we studied 206 twin pairs in Sydney to estimate the importance of genetic factors in alcohol metabolism and psychomotor sensitivity. Sib-pair linkage analysis suggests that variants in the class I ADH region on chromosome 4 account for at least half the genetic variation in ethanol metabolism. Most interesting is that the combined ADH2/3 genotype appears to account for about 6% of variance in alcohol consumption and dependence in men.

The role of HFE polymorphisms in iron metabolism in Australian twins
(N.G. Martin, G. Zhu, L.W. Powell in collaboration with J.B. Whitfield, Royal Prince Alfred Hospital, Sydney)
In 1993-95 blood samples were obtained from 3348 twins for whom extensive information on drinking, smoking and other lifestyle habits, and reproductive and menstrual history in women were available. Samples were assayed for serum iron, transferrin and ferritin and were typed for the CY and HD polymorphisms in the haemochromatosis gene, HFE. We are now quantifying the effects of all these variables on parameters of iron metabolism in the normal population.

Genetic Influences on Endometriosis
(S.A. Treloar, B. Haddon, S. Brooks, L. Swanso, N.G. Martin, G. Montgomery, in collaboration with V. O'Connor, University of Queensland and Dr. D. O'Connor)
We are investigating the genetic epidemiology of endometriosis. So far we have identified nearly 500 sister pairs with endometriosis and have obtained DNA samples from about 70% of these. The first 156 families have been typed with 400 markers and linkage analysis has begun. There are some intriguing early suggestions of linkage but we refuse to get excited by them until we have a larger sample.

Asthma and allergy in Australian twins and their families
(D.L. Duffy, N.G. Martin)
It is well known that asthma and atopy are interrelated, and that both aggregate within families, and there is currently much interest in the genetics of these conditions. In a collaborative agreement grant with AxyS Pharmaceuticals Inc. and with collaborators in Sydney, Melbourne and Perth, we have collected 800 sib pairs with asthma with the aim of performing a genome scan to find more major genes for asthma.

Osteoarthritis in ageing twins
(N.G. Martin, in collaboration with N. Bellamy, University of Queensland)
We have conducted a pilot study of 170 twins to assess the sensitivity and specificity of our questionnaire diagnosis compared with clinical and radiological examination in 50 affected and 50 unaffected pairs and analysis is underway. The long-term aim is to map major genes for osteoarthritis.

Psychosocial factors in cancer proneness in ageing twins
(K. Kirk, N.G. Martin)
A substantial private donation has enabled us to embark on a new longitudinal study of psychological and other psychosocial risk factors in disease proneness. A comprehensive questionnaire has been assembled which is being mailed to all twins aged 50 and over on the Australian Twin Register. In time, the data collected will be correlated with follow-up data on morbidity and mortality.

Genetic factors in anxiety, depression and fatigue
(A.J. Birley, N Gillespie, K Kirk, NG Martin in collaboration with Prof. I. Hickie, University of NSW)
Over 6000 twin pairs from two age cohorts have been asked about their psychiatric symptoms. Multivariate genetic analysis suggests that while there is some common genetic predisposition with anxiety and depression, somatisation appears to be partly genetically distinct. The focus of the work now moves to finding variables which modify this genetic risk, including life events, and measures of support from parents, spouses and friends. We are also carrying out a genome scan for genes influencing anxiety and depression in a collaboration with Gemini Genomics Ltd (UK).

Genetics of Male Pattern Baldness (MPB) as a potential risk factor for prostate cancer
(D.R. Nyholt, N.G. Martin)
Common pattern baldness (androgenetic alopecia, AGA) is the most common form of hair loss in humans. In Caucasians, normal male hair loss, commonly known as “male pattern baldness” (MPB), is noticeable in about 20% of men aged 20, and increases steadily with age, so that a male in his 90’s has a 90% chance of having some degree of MPB. In addition to being among the most common natural conditions that make men self-conscious, recent studies indicate associations of MPB with benign prostatic hyperplasia, and that MBP is a risk factor for clinical prostate cancer. Our results indicate that 81% of the total variance could be attributed to additive genetic effects (95%CI:77-85%). By studying families, we hope to understand more about how genes and environment influence natural hair loss (that is, not due to illness or medication) as well as other associated aspects of health.

Genetic analysis of migraine and comorbid psychiatric disorders using twin families.
(D.R. Nyholt, B.J. Mowry, N.G. Martin)
Typical migraine, is a frequent, debilitating and painful disorder that normally affects people during their most productive years (up to 25% of females and 7.5% of males in Western populations). Additionally, several studies have demonstrated a cross-sectional relation between psychiatric disorders (namely anxiety and depression) and migraine in community samples. This project will collect a sample with sufficient power to perform a genome wide linkage screen to i) identify novel susceptibility genes, and ii) confirm previously reported susceptibility genes for migraine and co-occurring psychiatric disorders. The susceptibility genes identified (and confirmed) in this sample will provide clues to the further elucidation of the complex molecular pathways of migraine (and co-occurring psychiatric disorders) and, finally, will help in the development of diagnostic tests and rational treatment strategies.

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Staff

For full list of staff and details click here

Funding

National Health & Medical Research Council
Queensland Cancer Fund
NIH (National Institute of Alcoholism and Alcohol Abuse - USA)
NIH (National Institute of Drug Abuse - USA)
NIH (National Cancer Institute - USA)
Human Frontiers Science Program - Japan
Borderline Personality Disorder Foundation

Collaborators

Professor Andrew Heath & Dr Pam Madden, Department of Psychiatry, Washington University Medical School, St Louis, U.S.
Professor Dorret Boomsma, Department of Biological Psychology, Free University, Amsterdam, Netherlands
Professor Jaakko Kaprio, Department of Public Health, University of Helsinki, Finland
Dr Lon Cardon, Wellcome Trust Institute of Human Genetics, Oxford, U.K.
Dr John Whitfield, Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney
Dr Rick Sturm, Institute of Molecular Bioscience, University of Queensland
Dr Mike Bailey, Department of Psychology, Northwestern University, Chicago, U.S.
Dr Richard Atkinson, University of Wisconsin, U.S.
Dr Elliot Nelson, Department of Psychiatry, Washington University, St Louis, Missouri, USA
Dr Timothy Trull, Department of Psychological Sciences, University of Missouri-Columbia, Columbia, USA
Dr Wendy Slutske, Department of Psychological Sciences, University of Missouri-Columbia, Columbia, USA
Dr Timoth Bates, University of Edinburgh, Edinburgh, UK

Projects for Students

We are keen to attract good PhD and Honours students in a wide range of topics in Genetic Epidemiology and Gene Mapping. We emphasise statistical and computer skills but offer training in necessary laboratory techniques for gene mapping as a minor theme. Major interests are in behaviour genetics (personality and cognition), psychiatric genetics (anxiety, depression, alcoholism, drug abuse) and common diseases including asthma, endometriosis, and melanoma.

Key Publications

Martin NG, Boomsma DI, Machin GA: A twin-pronged attack on complex traits. Nature Genetics 17:387-392, 1997.

Heath AC, Bucholz KK, Madden PAF, Dinwiddie SH, Slutske WS, Bierut LJ, Statham DJ, Dunne MP, Whitfield JB, Martin NG: Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men. Psychological Medicine 27:1381-1396, 1997.

Statham DJ, Heath AC, Madden PAF, Bucholz KK, Bierut LJ, Dinwiddie SH, Slutske WS, Dunne MP, Martin NG: Suicidal behaviour: an epidemiologic and genetic study. Psychological Medicine 28:839-855, 1998.

Whitfield JB, Nightingale BN, Bucholz KK, Madden PAF, Heath AC, Martin NG: ADH genotypes and alcohol use and dependence in Europeans. Alcoholism: Clinical and Experimental Research 22:1463-1469, 1998.

Zhu G, Duffy DL, Eldridge A, Grace M, Mayne C, O'Gorman L, Aitken JF, Neale MC, Hayward NK, Green AC, Martin NG: A major gene for mole density is linked to the familial melanoma gene CDKN2A: a maximum likelihood combined linkage and association analysis in twins and their families. American Journal of Human Genetics 65:483-492, 1999.

Palmer JS, Duffy DL, Box NF, Aitken JF, O’Gorman LE, Green AC, Hayward NK, Martin NG, Sturm RA: Melanocortin-1 receptor polymorphisms and risk of melanoma: Is the association explained solely by pigmentation phenotype? American Journal of Human Genetics 66:176-186, 2000.

Whitfield JB, Cullen L, Powell LW, Heath AC, Zhu G, Duffy DL, Martin NG: Effects of HFE C282Y and H63D polymorphisms and polygenic background on iron stores in a large community sample of twins. American Journal of Human Genetics 66:1246-1258, 2000.

Bailey JM, Dunne MP, Martin NG: Genetic and environmental influences on sexual orientation and its correlates in an Australian twin sample. Journal of Personality and Social Psychology 78:524-536, 2000.

Lake RIE, Eaves LJ, Maes HHM, Heath AC, Martin NG: Further evidence against the environmental transmission of individual differences in Neuroticism from a collaborative study of 45,850 twins and relatives on two continents. Behavior Genetics 30:223-233, 2000.

Montgomery GW, Duffy DL, Hall J, Kudo M, Martin NG, Hsueh AJ: Mutations in the follicle- stimulating hormone receptor and familial dizygotic twinning. Lancet 357:773-774, 2001.

Luciano M, Smith GA, Wright MJ, Geffen GM, Geffen LB, Martin NG: On the heritability of inspection time and its covariance with IQ: a twin study. Intelligence 29:443-457, 2001.

Wright MJ, Hansell NK, Geffen GM, Geffen LB, Smith, GA, Martin NG.Genetic influence on the variance in P3 amplitude and latency. Behavior Genetics 31:555-565, 2001.

Treloar SA, Heath AC, Martin NG: Genetic and environmental influences on premenstrual symptoms in an Australian twin sample. Psychological Medicine 32:25-38, 2002.

Wright MJ, Luciano M, Hansell NK, Geffen GM, Geffen LB, Martin NG: Genetic sources of covariation among P3(00) and online performance variables in a delayed-response working memory task. Biological Psychology 61:183-202, 2002.

Slutske WS, Heath AC, Madden PAF, Bucholz KK, Statham DJ, Martin NG: Personality and the genetic risk for alcohol dependence. Journal of Abnormal Psychology 111:124-133, 2002.