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Human Molecular Genetics Advance Access originally published online on September 6, 2004
Human Molecular Genetics 2004 13(19):2173-2182; doi:10.1093/hmg/ddh239
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Human Molecular Genetics, Vol. 13, No. 19 © Oxford University Press 2004; all rights reserved

Genome-wide linkage analysis of a composite index of neuroticism and mood-related scales in extreme selected sibships

Matthew W. Nash1,{dagger}, Patricia Huezo-Diaz1,{dagger}, Richard J. Williamson1, Abraham Sterne1, Shaun Purcell1,4, Farzana Hoda1, Stacey S. Cherny5, Gonçalo R. Abecasis6, Martin Prince2, Jeffrey A. Gray3, David Ball1, Philip Asherson1, Anthony Mann2, David Goldberg2, Peter McGuffin1, Anne Farmer1, Robert Plomin1, Ian W. Craig1,* and Pak C. Sham1,7

1MRC Social, Genetic and Developmental Psychiatry Research Centre, 2Section of Epidemiology and 3Department of Psychology, Institute of Psychiatry, King's College, London, UK, 4Whitehead Institute, Center for Genome Research, Cambridge, MA, USA, 5Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, 6Center for Statistical Genetics, University of Michigan, Ann Arbor, USA and 7Department of Psychiatry and Genome Research Centre, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China

Received April 20, 2004; Accepted July 21, 2004

There is considerable evidence to suggest that the genetic vulnerabilities to depression and anxiety substantially overlap and quantitatively act to alter risk to both disorders. Continuous scales can be used to index this shared liability and are a complementary approach to the use of clinical phenotypes in the genetic analysis of depression and anxiety. The aim of this study (Genetic and Environmental Nature of Emotional States in Siblings) was to identify genetic variants for the liability to depression and anxiety after the application of quantitative genetic methodology to a large community-based sample (n=34 371), using four well-validated questionnaires of depression and anxiety. Genetic model fitting was performed on 2658 unselected sibships, which provided evidence for a single common familial factor that accounted for a substantial proportion of the genetic variances and covariances of the four scales. Using the parameter estimates from this model, a composite index of liability (G) was constructed. This index was then used to select a smaller—but statistically powerful—sample for DNA collection (757 individuals, 297 sibships). These individuals were genotyped with more than 400 microsatellite markers. After the data were checked and cleaned, linkage analysis was performed on G and the personality scale of neuroticism using theregression-based linkage program MERLIN-REGRESS. The results indicated two potential quantitative trait loci (QTL): one on chromosome 1p (LOD 2.2) around 64 cM (43–70 cM) near marker D1S2892 and another on chromosome 6p (LOD 2.7) around 47 cM (34–63 cM) near marker D6S1610. Further exploratory sex-specific analyses suggested that these QTLs might have sex-limited effects.

* To whom correspondence should be addressed at: SGDP Centre, Institute of Psychiatry, De Crespigny Park, PO Box PO80 London SE5 8AF, UK. Tel: +44 2078480018; Fax: +44 2078480866; Email: i.craig{at}iop.kcl.ac.uk


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