title: White matter integrity as an intermediate phenotype: exploratory genome-wide association analysis in individuals at high risk of bipolar disorder.
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.
authors.affiliation: Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, UK. e.sprooten@ed.ac.uk
authors.forename: Emma
authors.initials: E
authors.lastname: Sprooten
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Fleming
authors.forename: Pippa A
authors.initials: PA
authors.lastname: Thomson
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bastin
authors.forename: Heather C
authors.initials: HC
authors.lastname: Whalley
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hall
authors.forename: Jess E
authors.initials: JE
authors.lastname: Sussmann
authors.forename: James
authors.initials: J
authors.lastname: McKirdy
authors.forename: Douglas
authors.initials: D
authors.lastname: Blackwood
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lawrie
authors.forename: Andrew M
authors.initials: AM
authors.lastname: McIntosh
mesh_terms: D000293:Adolescent; D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000502:physiology* / Q000503:physiopathology; D016022:Case-Control Studies; D056324:Diffusion Tensor Imaging; D058068:Endophenotypes; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008957:Models, Genetic; D009413:Nerve Fibers, Myelinated / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D055815:Young Adult