The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI

Abstract

Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD.

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

“…This group has also reported polygene associations with limbic brain activation during functional MRI [Whalley et al, 2012], and white matter integrity measures from DTI in a bipolar at‐risk cohort [Whalley et al, 2012]. Neuroimaging biomarkers have previously been identified in the Australian at‐risk subjects which were part of the current study, with a lack of recruitment of the inferior frontal gyrus in the high‐risk participants compared to healthy controls during an fMRI emotion inhibition task [Roberts et al, 2013].…”

“…However, despite phenotypic aggregation within families [McGuffin et al, 2003; Lichtenstein et al, 2009], no studies have so far examined polygenic risk incorporating these common genetic factors in a family context in adults, with only one group to date reporting on polygenic risk in adolescent offspring of individuals with BP [Whalley et al, 2012, 2013]. …”

Structural and Functional Neuroimaging Studies in Major Depressive Disorder With Psychotic Features: A Critical Review

“…41,118,119 Moreover, because a polygenic contribution to MDD with psychotic features can be expected, future genomewide association studies on representative samples MDD with psychotic features may afford quantitative risk scores to be subsequently used in studies investigating the relationship between robust imaging phenotypes and polygenic risk scores. 120,121 Finally, there should also be neuroimaging studies applying a dimensional approach to the evaluation of psychosis associated with MDD, with both subthreshold and full-blown psychotic experiences rated along a continuum of severity, on a background of major depressive symptoms. There is a significant prevalence of subthreshold psychotic-like experiences in the general population 122 and in subjects with less severe major depressive episodes, 123 and there is a growing recognition that psychotic symptoms may best be viewed as falling along a continuum of severity in MDD rather than solely as a subcategory of severe MDD.…”

Polygenic risk scores in imaging genetics: Usefulness and applications

“…Whalley et al (2012) showed a positive correlation between bipolar disorder PRS and activation of the ACC, amygdala and other limbic regions of the brain, areas that have been impaired in bipolar disorder expression. In the same cohort, the bipolar disorder PRS was significantly associated with decreased white matter integrity in the right superior longitudinal fasciculus (Whalley et al, 2013).…”

“…Recently, the bipolar disorder PRS has been used to examine its relationship with brain function and structure in individuals at familial risk for a mood disorder (Whalley et al, 2012;2013). Whalley et al (2012) showed a positive correlation between bipolar disorder PRS and activation of the ACC, amygdala and other limbic regions of the brain, areas that have been impaired in bipolar disorder expression.…”