title: Effects of a mis-sense DISC1 variant on brain activation in two cohorts at high risk of bipolar disorder or schizophrenia.
abstract: Bipolar disorder and schizophrenia share a number of clinical features and genetic risk variants of small effect, suggesting overlapping pathogenic mechanisms. The effect of single genetic risk variants on brain function is likely to differ in people at high familial risk versus controls as these individuals have a higher overall genetic loading and are therefore closer to crossing a threshold of disease liability. Therefore, whilst the effects of genetic risk variants on brain function may be similar across individuals at risk of both disorders, they are hypothesized to differ compared to that seen in control subjects. We sought to examine the effects of the DISC1 Leu(607) Phe polymorphism on brain activation in young healthy individuals at familial risk of bipolar disorder (n = 84), in a group of controls (n = 78), and in a group at familial risk of schizophrenia (n = 47), performing a language task. We assessed whether genotype effects on brain activation differed according to risk status. There was a significant genotype × group interaction in a cluster centered on the left pre/postcentral gyrus, extending to the inferior frontal gyrus. The origin of this genotype × group effect originated from a significant effect of the presumed risk variant (Phe) on brain activation in the control group, which was absent in both high-risk groups. Differential effects of this polymorphism in controls compared to the two familial groups suggests a commonality of effect across individuals at high-risk of the disorders, which is likely to be dependant upon existing genetic background.
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK. heather.whalley@ed.ac.uk
authors.forename: Heather C
authors.initials: HC
authors.lastname: Whalley
authors.forename: Jessika E
authors.initials: JE
authors.lastname: Sussmann
authors.forename: Mandy
authors.initials: M
authors.lastname: Johnstone
authors.forename: Liana
authors.initials: L
authors.lastname: Romaniuk
authors.forename: Holly
authors.initials: H
authors.lastname: Redpath
authors.forename: Goultchira
authors.initials: G
authors.lastname: Chakirova
authors.forename: Prerona
authors.initials: P
authors.lastname: Mukherjee
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hall
authors.forename: Eve C
authors.initials: EC
authors.lastname: Johnstone
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lawrie
authors.forename: Andrew M
authors.initials: AM
authors.lastname: McIntosh
mesh_terms: D000328:Adult; D001519:Behavior; D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D016022:Case-Control Studies; D016000:Cluster Analysis; D015331:Cohort Studies; D003710:Demography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D013647:Task Performance and Analysis; D055815:Young Adult
chemical_list: C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins