Molecular Psychiatry Laboratory

Corinne Lendon Staff
Funding
Collaborators
Key Recent Publications
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Lab Head: Dr Corinne Lendon

Brain cells SCHIZOPHRENIA RESEARCH

The Molecular Psychiatry Laboratory has a close association with Professor Bryan Mowry, Director, Genetics Research Program, Queensland Centre for Mental Health Research and hosts a laboratory group headed by Associate Professor Mowry researching schizophrenia.

Schizophrenia (SZ) Research group is involved in the establishment and collection of large patient and control cohorts. The main focus is to identify chromosomal regions that contain genes that predispose to SZ. Whole genome wide single nucleotide polymorphism genotyping is carried out in large cohorts of patients and controls using the Illumina platform. The extensive patient and control collections are from Australian, India, Sarawak and Fiji. An important international contribution is made with some of these cohorts in a major US led collaborative effort to find genes for SZ.

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 17;

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 Feb 15;16(4):364-73.

Holliday EG, Handoko HY, James MR, McGrath JJ, Nertney DA, Tirupati S, Thara R, Levinson DF, Hayward NK, Mowry BJ, Nyholt DR. Association study of the dystrobrevin-binding gene with schizophrenia in Australian and Indian samples. Twin Res Hum Genet. 2006 Aug;9(4):531-9

DEMENTIA RESEARCH

The Molecular Psychiatry Group investigates factors that modifying susceptibility for dementia, especially Alzheimer's disease and related neurological and psychiatric disorders, including psychosis and depression.

One project involves a study of the carers of dementia patients. Some carers cope well with their role but others become overburdened and develop depressive symptoms themselves. So far we have revealed that carer burden is heightened by carers feelings of role captivity, a diminished confidence in their role and poor patient relationship quality (accepted Int J Geeriatric Psychiatry).

The molecular investigations of the lab are aimed at discovering factors that predispose to or protect individuals from dementia and Alzheimer's disease. Much of the current drug discovery programs in Alzheimer's disease are aimed at mechanisms inspired by the rare familial forms caused by single-gene mutations. Our focus is on the most common forms that are inherited in a non-Mendelian complex/sporadic manner.

Our other projects are hunting for novel genes and investigating the mechanisms that incur risk for the above disorders using association strategies and in vitro modeling of their effects and interactions.

Our case-control cohorts together with those of our European collaborators extend our cases and controls to over 4000. The novel and candidate genes arising from this work are further investigated using genotype-phenotype studies that incorporate variables including neuropathological measures, response to treatment, patient and carer well-being, memory and neuropsychological measures. The behavioural and psychological symptoms of AD occur in some but not all patients. When they do occur they cause both patient and carers considerable distress. We are studying genes that have been implicated in psychosis and depression, including neuregulin 1 and those of the serotinergic and catecholaminergic systems, to determine whether they influence the presence and severity of symptoms.

Our in vitro models incorporate expression systems, as well as human brain cells and patient lymphoblasts are used to investigate the molecular mechanisms of interaction between gene-environment factors known to be involved in predisposition to dementia and those that we and our collaborators discover.

Staff

Labhead:	Dr Corinne Lendon
Post Doc:	Dr Antonia Pritchard
Visiting Scientist:	Professor Bryan Mowry
Research Assistants:	Cheryl Fillipich Heather Smith

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Funding

NHMRC
Judith Jane Masons and Harold Stannett Williams Memorial Foundation

Collaborators

Prof David Mann
Dr Jean-Charles Lambert
Prof David St Clair
Dr Marie-Christine Chartier-Harlin

Staff members in this group are:

Cheryl Filipich
Herlina Handoko
Nick Matigian
Heather Smith

Key Publications

Key Publications Clark R, Hutton M, Fuldner R, Karran E, Talbot, C, Froelich S, Adams M, Lendon CL, et al (Alzheimer's Disease Collaborative Group) (1995) The structure of Presenilin 1 and mutations in Alzheimer's Disease. Nature Gen 11, 219-222

Wragg M, Hutton M, Talbot CJ, Busfield F, Sang Woo Han, Lendon CL, Clark R,Morris JC, Edwards D, Pfeiffer E, Rossor M, Crook R, Prihar G, Philips H, Baker M, Houlden H, Roberts G, Karran E, Craddock N, Goate AM, Hardy J (1996) Genetic association between an intronic polymorphism in the presenilin 1 (PS-1) gene and late onset Alzheimer's Disease. Lancet 347, 509-512

Lemere C A, Lopera F, Kosik K S, Lendon CL, et al The E280A Presenilin 1 Mutation Leads to A Distinct Alzheimer's Phenotype: Increased A?42 Deposition and Severe Cerebellar Pathology (1996) Nature Medicine 2(10) 1146-1150

Lopera F, Ardilla A, Martinez A, Madrigal L, Arango-Viana JC, Lemere C, Arango-Lasprilla JC, Hincapie M, Arcos-Burgos MD, Ossa JE, Behrens IM, Norton J, Lendon CL, Goate AM, Ruiz-Linares A, Rosselli M, Kosik KS (1997). Phenotypic features of a very large kindred with a E280A presenilin 1 mutation in Antioquia, Colombia JAMA 277 (10), 793-799

Lendon CL, Martinez A, Behrens IM, Kosik K, Madrigal L, Norton J, Neuman R, Myers A, Busfield F, Wragg M, Arcos M, Arrango Viana JC, Ruiz A, Ossa J, Morris JC, Goate AM, Lopera F. A mutation in the presenilin 1 gene causes familial early onset Alzheimer's disease in a Colombian population: a founder effect enables assessment of phenotype modulation on a homogenous genetic background. (1997) Human Mutation 10; 186-195.

Foster NL, Wilhelmsen K, Sima AAF, Jones MZ, D'Amato C, Gilman S, conference contributors, Lendon C, Sima A. Frontotemporal dementia and Parkinsonism linked to chromosome 17: A consensus Ann Neuro. (1997) l; 41:706-715

Lendon CL, Ashall F, Goate AG. (1997) Exploring the etiology of Alzheimer's Disease using molecular genetics. JAMA 277 (10) 825-831

Craddock N & Lendon C New susceptibility gene for Alzheimer's disease on chromosome 12? Lancet. 1998 28;352(9142):1720-1

Artiga MJ, Bullido MJ, Frank A, Sastre I, Recuero M, Garcia MA, Lendon CL, Han SW, Morris JC, Vazquez J, Goate A, Valdivieso F. Risk for Alzheimer's disease correlates with the transcriptional activity of the APOE gene Human Molecular genetics 1998; 7(9):1506-10

Bullido MJ, Artiga MJ, , Recuero M, Sastre I, Garcia MA, Alududo J, Lendon C, Han SW, Morris JC, Frank A, Vazquez J, Goate A, Valdivieso F. A polymorphism in the transcriptional regulatory region of apolipoprotein E gene associated with risk for dementia of the Alzheimer's type. Nature Genetics 1998; 18: 69-71

Lendon CL, Lynch T, Norton J, McKeel DW Jr, Busfield F, Craddock N, Chakraverty S, Gopolakrishnan G, Shears SD, Grimmett W, Wilhelmsen K, Goate AM, Morris JC. Hereditary Dysphasic Disinhibition Dementia: a frontal lobe dementia linked to 17q21-22. Neurology 1998 50(6) 1546-1555.

Mike Hutton*, Corinne L. Lendon*, Patrizia Rizzu*. et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393 (1998) 702-705 * contributed equally to this work:

Natasha Coyle, Ian Jones, Emma Robertson, Corinne Lendon, Nick Craddock Variation at the serotonin transporter gene influences susceptibility to Bipolar affective puerperal psychosis Lancet 2000 Oct 28;356(9240):1490-1.

Jean-Charles Lambert, Louisa Goumidi, Fabienne Wavrant-De Vričze, Bernard Frigard, Judith M Harris, Alistair Cummings, John Coates, Florence Pasquier, Dominique Cottel, Marianne Gaillac, David St Clair, David MA Mann, John Hardy, Corinne L Lendon, Philippe Amouyel, Marie-Christine Chartier-Harlin. The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer's disease. Hum. Mol. Genet. 2000;9 2275-2280

Lendon CL, Byung Hee Han, Kayvon Salimi, Behrens MI, Muller MC, Fagan AM, Holtzman DM. No effect of apolipoprotein E on neuronal cell death due to excitotoxic and apoptotic agents in vitro and to hypoxic ischaemia in vivo. European Journal of Neuroscience, 2000; 12 (7), 2235-2242

J-C Lambert, DMA Mann, L Goumidi, J Harris, P Amouyel, T Iwatsubo, CL Lendon, M-C Chartier-Harlin. Impact of the APOE promoter polymorphisms on A? deposition in Alzheimer's disease Lancet 2001; 357; 608-609

J-C Lambert, D Mann, J M Harris, H Lemmon, M-C Chartier-Harlin, A Cummings, D St-Clair, T Iwatsubo, C Lendon. The -48 CT polymorphism in the presenilin 1 promoter associated with risk of developing Alzheimer's disease and increase of A? load in brain J Med Gen 2001; 38:353-355

Lendon C, Craddock N. Is LBP-1c/CP2/LSF a disease-modifying gene for Alzheimer's disease? Lancet. 2001 Sep 29;358(9287):1029-30.

Corinne Lendon, Nick Craddock. Susceptibility gene(s) for Alzheimer's disease on chromosome 10. Trends in Neurosciences, 2001, 24:10:557-559

JC Lambert, L Goumidi, L Myllykangas, F Wavrant-De Vričze, J Wang, M J Bullido, J M Harris, M J Artiga, D Hernandez4, J M. Kwon, B Frigard, R Peterson, A Cumming, F Pasquier, T Polvikoski, I Sastre, P Tienari, A Frank, R Sulkava, J C Morris, D St Clair, DM Mann, P Amouyel, J Hardy, F Valdivieso, A M Goate, M Haltia, J Pérez-Tur, C L Lendon, M-C Chartier-Harlin. Contribution of APOE promoter polymorphisms to Alzheimer's disease risk. Neurology. 2002 9;59(1):59-66

E Green, J Harris, J-C Lambert, D Mann, MC Chartier-Harlin, D St Clair, H Lemmon, T Iwatsubo, C Lendon. Interleukin-1 promoter polymorphisms, A? deposition and the risk for Alzheimer's disease. Neurology 2002; 58: 1566-8

Lendon CL, Judith Harris, Antonia Pritchard, Graham Teasdale, James Nicoll,. Gordon Murray. Influence of APOE promoter polymorphisms on outcome after head injury Neurology 2003 Sep 9;61(5):683-685

Haynes LE, Lendon CL, Barber DJ, Mitchell I. 17 Beta-oestradiol attenuates dexamethasone-induced lethal and sublethal neuronal damage in the striatum and hippocampus. Neuroscience. 2003;120(3):799-806.

Lambert J-C, Coyle N, Lendon C. Allelic modulation of APOE by estrogen. J. Med Genetics 2004 41(2):104-12

Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P; AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial Lancet 2004 363:2105-15

B. Joy Snider, Joanne Norton, Mary A. Coats, Sumi Chakraverty, Craig. E. Hou, Ramiro Jervis, Corinne L. Lendon, Alison M. Goate, Daniel W. McKeel, Jr, John C. Morris, MD. A novel presenilin 1 mutation (S170F) causing Alzheimer's disease with Lewy bodies in the third decade of life. Arch Neurol. 2005 Dec;62(12):1821-30

Pritchard A, Mann D, St Clair D, Whalley L, Lendon C. Meta Analysis of LRP exon 3 polymorphism in Alzheimers disease from 18 cohort studies plus an original independent report. Neurosci Lett. 2005: 15;382(3):221-6

Lambert D, Middle F, Hamshere ML, Segurado R, Raybould R, Corvin A, Green E, O'mahony E, Nikolov I, Mulcahy T, Haque S, Bort S, Bennett P, Norton N, Owen MJ, Kirov G, Lendon C, Jones L, Jones I, Holmans P, Gill M, Craddock N. Stage 2 of the Wellcome Trust UK-Irish bipolar affective disorder sibling-pair genome screen provides evidence for suggestive linkage on chromosomes 6q16-q21 and 4q12-q21. Molecular Psychiatry, 2005, 10(9):831-41.

Antonia L. Pritchard, Colin W. Pritchard, Sayeed Haque, Roger Holder, Peter Bentham, Corinne L. Lendon The impact of APOE gene polymorphisms and haplotypes on behavioural and psychological symptoms in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2006 Oct in press

Campbell, P., Wright, J., Job, D., Crome, P., Schulz, J., McCabe, J., Jones, L., Oyebode, J., Bentham, P., Lendon, C Determinants of burden in those who care for someone with dementia. Int J Geriatric Psychiatry In press 2008.