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.
.
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).
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