·         About Genetics Research at QCMHR

·         Genetics Projects

·         Genetics Publications

 

Funding

Our research program is supported by funding from:

Queensland Health

Ipswich Hospital Foundation

Australian National Health and Medical Research Foundation

US National Institute of Mental Health

Stanley Medical Research Institute

Rebecca L Cooper Medical Research Foundation

 

 

Staff

Director - A/Prof Bryan Mowry For Biography Click Here

Elizabeth Holliday, PhD (Statistical Genetics)

Duncan McLean, MA (Public Sector Leadership)

Deborah Nertney, BSc (Microbiology)

Heather Smith, BSc (Microbiology)

Cheryl Filippich, BAppSc (Medical Technology)

Suzanne Manning, MSc (Biochemistry) 

About Our Work

There is good evidence from family studies that genes play an important causative role in the development of schizophrenia. The role has been confirmed in twin and adoption studies, but the pattern of inheritance is complex. Available data suggest multiple genes, each exerting small to moderate effect on overall disease risk, interacting with environmental factors in a neurodevelopmental context to confer vulnerability. Potential environmental factors include: retroviral (RNA) elements discovered in patients' cerebro-spinal fluid and expressed in frontal brain cortex samples; higher risk reported with urban versus rural birth; and perinatal factors.

The molecular genetic revolution has greatly accelerated the ability to search for disease genes. Prior to the mid 1970's, the only markers available for mapping diseases were blood groups, serum proteins and HLA tissue types relating to only a handful of chromosomal locations. With the discovery of certain enzyme's ability to cut DNA by recognizing specific sequences of 4-6 base pairs in length, restriction fragment length polymorphisms (RFLPs) were created for use as genome-wide markers for mapping disease genes. Polymerase chain reaction (PCR) methodology made it possible to amplify genome-wide, highly polymorphic microsatellite markers (STRPs), superseding RFLPs. Single nucleotide polymorphisms (SNPs) involving a single base change, are now also being utilized because they are easily detected, adaptable to high throughput, automated typing, and they are abundant, occurring one in every 1000 base pairs, based on results of the Human Genome Project and Celera Genomics.

Our work is aimed at identifying susceptibility genes for schizophrenia and related disorders. We are studying both ethnically diverse (heterogeneous) and genetically isolated (homogeneous) populations, to account for two different possibilities: (1) that the same, frequently occurring causative genes occur in all populations and (2) that rare genes may exist in one or more genetically homogeneous populations. We also pay attention to refining the phenotype while applying the latest molecular genetic and analytic techniques to large multicentre studies and to population isolates.

 

Research Program

Past Projects

Molecular genetics of schizophrenia in a US/Australian case/control cohort

This study was funded by the NHMRC and conducted between 1991 and 1999.  Over 1000 families were screened for possible inclusion based on family history of disease. From this screening sample, 45 Australian families with multiple affected members were included. A genome screen on the first 43 pedigrees (the first 18 Australian, plus 25 US pedigrees), using a map of over 300 genetic markers, was conducted in 1996. Regions on chromosomes 2q, 4q, 9q, 10q and 11q provided nominal evidence that they may contain factors associated with inheritance of vulnerability to schizophrenia. Follow up fine mapping supported the initial findings for schizophrenia susceptibility regions on chromosomes 2 and 10. 

 

Molecular genetics of schizophrenia in a US/Australian sib-pair cohort

Funded by the NIMH, a collaboration of nine centres (QCMHR and eight US sites) was established to recruit 500 independent affected sib pairs (ASPs) with schizophrenia to carry out molecular and linkage analyses.

By the completion of the study in 2003, we had recruited eighty five ASPs from within Australia . A total of 535 ASPs were recruited from the entire collaboration. Outcomes of this study will be published in mid-2005.

 

Molecular genetics of psychosis in Fiji

Indigenous Fijians and Fijian Indians (originally imported as indentured labourers from India 80 to 120 years ago) represent two distinct populations. We have collected a sample of Indigenous Fijian (partially genetically isolated) and Indian Fijian subjects with psychotic disorders for future gene mapping studies using linkage disequilibrium analysis.  Approximately 600 subjects (probands plus available parents and siblings) were recruited from St Giles Hospital, Suva , and diagnostically ascertained. Another 100 (50 from each population) non-psychotic control subjects were recruited to determine allele frequencies for gene studies. 

 

Although recruitment for the above studies is complete, data will be included in future candidate gene studies in our own lab and together with collaborating labs.

 

Ongoing Projects

Molecular genetics of schizophrenia in a US/Australian case/control cohort

QCMHR is one of ten collaborating sites which together has received an additional four years of funding from the NIMH to recruit a large cohort of individuals with a diagnosis of schizophrenia, plus matched controls without psychosis. The Australian recruitment target is 1000 affected individuals over three years. When complete, this will be the largest sample ever recruited for genetics studies in schizophrenia.

 

Based on these data, extensive genetic analyses will be carried out to refine the search for schizophrenia susceptibility genes. We will select positive regions in our genome scan of the ASP sample, and then develop single nucleotide polymorphism (SNP) maps across these regions using information from public databases and from our own SNP discovery. Analyses will be used to evaluate evidence for genetic association, and identify candidate genes to be studied. Subsidiary analyses will be carried out on subsets of families identified based on the distribution of critical variables such as age of onset and typical quality of symptoms.

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Download Documentation

Molecular Genetics Information Sheet (.pdf)

Molecular Genetics Brochure (.pdf)

This study is in its second year of operation.

 

Australian twin pairs study

Adoption and twin studies have been crucial for establishing the genetic basis for psychotic disorders, both schizophrenia and bipolar disorder. Funded by the Stanley Foundation (USA) and the NHMRC, this project aims to collect a sample of about 80 twins, male and female, monozygotic and dizygotic, each of whom has at least one member with a psychotic disorder. A sample of about 45 control twins where both members are unaffected will also be collected. We aim to investigate the role of genetic and non-genetic risk factors, and behavioural markers reportedly associated with psychotic disorders. The study will include a series of neurocognitive and neurophysiological assessments and Magnetic Resonance Imaging (MRI) scans, with the goal of clarifying the psychotic phenotype(s) for genetic analyses.

 

Download Documentation.

Twin Pairs Study Information sheet (.pdf)

Twin Pairs Study Brochure (.pdf)

 

This study is in its third year of operation.

 

Molecular genetics of schizophrenia in the Iban of Sarawak

The Iban are indigenous people of Malaysia who have remained genetically distinct through geography and limited contact by outsiders. The aims of this study are to identify extended families containing more than one individual with schizophrenia; then to confirm these diagnoses by standardised research interviews, to gather systematic data on relatives affected by schizophrenia, and to take blood samples from these individuals and relevant family members.  The long-range goal is to identify a major gene that contributes to a vulnerability to schizophrenia in this restricted gene-pool.

 

In the first phase of this study, analysis of medical record data indicated that treated rates of schizophrenia among the Iban were higher than the reported prevalence for many populations at risk, including many small-scale societies, although different methodological approaches may partly explain these findings. Given the cultural patterns of treatment seeking behaviour, treated rates of schizophrenia reported here may closely approximate the population prevalence of this disorder. These results, together with previous fieldwork documenting extended pedigrees, have provided the epidemiological basis for the molecular genetic phase of our study, which is currently under way.

 

Now in its 4 th year, recruitment is still ongoing for this study and is expected to be complete by 2005.

 

Genetic study of schizophrenia in various caste populations of Tamil Nadu, India

The Brahmin people of Tamil Nadu are a partially isolated group who, like the Iban, seem an important population to sample for genetic studies. One hundred and six Affected Sibling Pair (ASP) families and 121 complete trios were recruited by 2004. Since then 50 male individuals from each of four castes have been recruited for genetic evolutionary studies, and for allele frequency determination for our schizophrenia genome-wide and fine-mapping studies. Recruitment is ongoing with a recruitment target of 400 ASP families and 400 trios.

 

PUBLICATIONS

 

 

Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe'er I, Dudbridge F, Holmans PA, Whittemore AS, Mowry BJ, Olincy A, Amin F, Cloninger CR, Silverman JM, Buccola NG, Byerley WF, Black DW, Crowe RR, Oksenberg JR, Mirel DB, Kendler KS, Freedman R, Gejman PV. Common variants on chromosomes 6p22.1 and 3q.26.33 are associated with schizophrenia. Accepted for publication, Nature, June 2009.

 

Holliday EG, McLean DE, Nyholt DR, Mowry BJ. Latent class analysis identifies a susceptibility locus on chromosome 1q23-25 for a schizophrenia subtype resembling deficit schizophrenia. Accepted for publication, Arch Gen Psychiatry February 2009.

 

Xing J, Watkins, WS, Witherspoon DJ, Zhang Y, Guthery SL, Mowry BJ, Thara R, Bulayeva K, Weiss RB, Jorde LB. Fine-Scaled Human Genetic Structure Revealed by SNP Microarrays. Accepted for publication, Genome Research January 2009.

 

Thara R, Srinivasan T, John S, Nancarrow D, Chant D, Holliday E, Mowry B. Design and clinical characteristics of a homogeneous schizophrenia pedigree sample from Tamil Nadu, India. Accepted for publication, Aust NZJ Psychiatry December 2008.

 

Holmans PA, Riley B, Pulver AE, Owen MJ, Wildenauer DB, Gejman PV, Mowry BJ, Laurent C, Kendler KS, Nestadt G, Williams NM, Schwab SG, Sanders AR, Nertney D, Mallet J, Wormley B, Lasseter VK, O’Donovan MC, Duan J, Albus M, Alexander M, Godard S, Ribble R, Liang KY, Norton N, Maier W, Papadimitriou G, Walsh D, Jay M, O'Neill A, Lerer FB, Dikeos D, Crowe RR, Silverman JM, Levinson DF. Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms. Mol Psychiatry. 2009 Feb 17. [Epub ahead of print]

 

Watkins WS, Thara R, Mowry BJ, Zhang Y, Witherspoon  DJ, Tolpinrud W, Bamshad MJ, Tirupati S, Padmavati R, Smith H, Nancarrow, D, Filippich C, Jorde LB. Genetic variation in South Indian castes: evidence from Y-chromosome, mitochondrial, and autosomal polymorphisms. BMC Genetics; 2008; 9:86.

 

Ng MYM, Levinson DF, Faraone SV, Suarez BK, DeLisi LE, Arinami T, Riley B, Paunio T, Pulver AE, Irmansyah, Holmans PA, Escamilla M, Wildenauer DB, Williams NM, Laurent C, Mowry BJ, Brzustowicz L, Maziade M, Sklar P, Garver DL, Abecasis G, Lerer B, Fallin MD, Gurling HMD, Gejman PV, Lindholm E, Moises H, Byerley W, Wijsman EM, Forabosco P, Tsuang MT, Hwu H-G, Okazaki Y, Kendler KS, Wormley B, Fanous A, Walsh D, O'Neill A, Peltonen L, Nestadt G, Lasseter VK, Liang KY, Papadimitriou G, Dikeos D, Schwab SG, Owen MJ, O’Donovan MC , Norton N, Hare E, Raventos H, Nicolini H, Albus M, Maier W, Nimgaonkar VL, Terenius L, Mallet J, Jay M, Godard S, Nertney D, Alexander M, Crowe RR, Silverman JM, Bassett AS, Roy M-A, Mérette C, Pato CN, Pato MT, Roos J Louw, Kohn Y, Amann-Zalcenstein D, Kalsi G, McQuillin A, Curtis D, Brynjolfson J, Sigmundsson T, Petursson H, Sanders AR, Duan J, Jazin E, Myles-Worsley M, Karayiorgou M and Lewis CM. Meta-analysis of 32 genomewide linkage studies of schizophrenia. Accepted for publication, Mol Psychiatry November 2008.

 

Holliday EG, Nyholt DR, Tirupati S, John S, Ramachandran P, Ramamurti M, Ramadoss AJ, Jeyagurunathan A, Kottiswaran S, Smith H, Filippich C, Nertney D, Watkins W S, Jorde LB, Thara R, Mowry BJ. Strong evidence for a novel schizophrenia risk locus in 1p31.1 in homogeneous pedigrees from Tamil Nadu, India. Am J Psychiatry 2009; Feb;166(2):206-15. Epub 2008 Oct 1.

 

Jones AL, Holliday EG, Mowry BJ, McLean DE, McGrath JJ, Pender MP, Greer JM. CTLA-4 single-nucleotide polymorphisms in a Caucasian population with schizophrenia. Brain Behav Immun  2009; 23:347–350. Epub 2008 Sep 26.

 

O'Donovan MC, Norton N, Williams H, Peirce T, Moskvina V, Nikolov I, Hamshere M, Carroll L, Georgieva L, Dwyer S, Holmans P, Marchini JL, Spencer CC, Howie B, Leung HT, Giegling I, Hartmann AM, Möller HJ, Morris DW, Shi Y, Feng G, Hoffmann P, Propping P, Vasilescu C, Maier W, Rietschel M, Zammit S, Schumacher J, Quinn EM, Schulze TG, Iwata N, Ikeda M, Darvasi A, Shifman S, He L, Duan J, Sanders AR, Levinson DF, Adolfsson R, Osby U, Terenius L, Jönsson EG, Cichon S, Nöthen MM, Gill M, Corvin AP, Rujescu D, Gejman PV, Kirov G, Craddock N, Williams NM, Owen MJ, Molecular Genetics of Schizophrenia Collaboration. Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2. Mol Psychiatry 2008 September 23. [Epub ahead of print]

 

O'Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V, Nikolov I, Hamshere M, Carroll L, Georgieva L, Dwyer S, Holmans P, Marchini JL, Spencer CC, Howie B, Leung HT, Hartmann AM, Möller HJ, Morris DW, Shi Y, Feng G, Hoffmann P, Propping P, Vasilescu C, Maier W, Rietschel M, Zammit S, Schumacher J, Quinn EM, Schulze TG, Williams NM, Giegling I, Iwata N, Ikeda M, Darvasi A, Shifman S, He L, Duan J, Sanders AR, Levinson DF, Gejman PV; Molecular Genetics of Schizophrenia Collaboration, Gejman PV, Sanders AR, Duan J, Levinson DF, Buccola NG, Mowry BJ, Freedman R, Amin F, Black DW, Silverman JM, Byerley WF, Cloninger CR, Cichon S, Nöthen MM, Gill M, Corvin A, Rujescu D, Kirov G, Owen MJ. Identification of loci associated with schizophrenia by genomewide association and follow-up. Nat Genet 2008; Sep;40(9):1053-5.

 

Matigian N, McCurdy R,  Feron F, Perry C, Smith H, Filippich C, McLean D, McGrath,J, Mackay-Sim A, Mowry B, Hayward N (2008).  Fibroblast and lymphoblast gene expression profiles in schizophrenia: are non-neural cells informative? PLoS One; Jun 11;3(6):e2412.

 

Sanders AR, Duan J, Levinson DF, Shi J, He D, Hou C, Burrell GJ, Nertney DA, Olincy A, Rozic P, Buccola N, Mowry BJ, Freedman R, Amin F, Black DW, Silverman JM, Byerley WF, Crowe RR, Cloninger CR, Martinez M, Gejman PV.  Testing Candidate Gene Hypotheses in a Large European Ancestry Case Control Sample. Am J Psychiatry 2008; 165(4):497-506.

 

Holliday E, Mowry B, Nyholt D.  A Reanalysis of 409 European-Ancestry and African American Families with Schizophrenia Reveals Significant Linkage to 8p23.3 with Evidence of Locus Heterogeneity. Am J Med Genet B Neuropsychiatr Genet 2008 Oct 5;147B(7):1080-8.

 

Matigian N, Windus L, Smith H, Filippich C, Pantelis C, McGrath J, Mowry B, Hayward N. Expression profiling in monozygotic twins discordant for bipolar disorder reveals dysregulation of the WNT signalling pathway.  Mol Psychiatry 2007; 12(9):815-25.

McRae AF, Matigian NA, Vadlamudi L, Mulley JC, Mowry B. Martin NG, Berkovic SF, Hayward NK, Visscher PM.  Replicated effects of sex and genotype on gene expression in human lymphoblastoid cell lines. Hum Mol  Genet 2007; 16(4):364-373. 

•  Holliday, E., MOWRY , Bryan J., Chant, D., Nyholt, D.(2005). The Importance of Modelling Heterogeneity in Complex Disease: Application to NIMH Schizophrenia Genetics Initiative Data. Human Genetics. (In press – accepted January 19, 2005).