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White matter integrity as an intermediate phenotype: Exploratory genome-wide association analysis in individuals at high risk of bipolar disorder

Author(s): E. Sprooten, K. M. Fleming, P. A. Thomson, M. E. Bastin, H. C. Whalley, J. Hall, J. E. Sussmann, J. McKirdy, D. Blackwood, S. M. Lawrie, A. M. McIntosh

Abstract:
White matter integrity, as measured using diffusion tensor imaging (DTI), is reduced in individuals with bipolar disorder (BD), their unaffected relatives and carriers of specific risk-alleles. Fractional anisotropy (FA), an index of white matter integrity, is highly heritable but the genetic architecture of this trait has received little investigation. In this study we performed a genome-wide association study with FA as quantitative phenotype, in unaffected relatives of patients with BD (N=70) and a matched control group (N=80). Amongst our top results were SNPs located in genes involved in cell adhesion, white matter development and neuronal plasticity. Pathway analysis of the top associated polymorphisms and genes confirmed the enrichment of processes relevant to BD and white matter development, including axon guidance, ErbB-signalling neurotrophin signalling, phosphatidylinositol signalling, and cell adhesion. The majority of genes implicated in these pathways were differentially associated with FA in individuals at high familial risk, suggesting interactions with genetic background or environmental factors secondary to familial risk for BD. Although the present findings require independent replication, the results encourage the use of global FA as a quantitative phenotype in future large-scale studies which may help to identify the biological processes underlying reduced FA in BD and other psychiatric disorders. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Full version: Available here

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ISBN: 0165-1781
Publication Year: 2013
Periodical: Psychiatry Research
Periodical Number: 2-3
Volume: 206
Pages: 223-231
Author Address: Sprooten, E Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Kennedy Tower,Morningside Pk, Edinburgh EH10 5HF, Midlothian, Scotland Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland Univ Edinburgh, Mol Med Ctr, Edinburgh EH10 5HF, Midlothian, Scotland Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh EH10 5HF, Midlothian, Scotland