Abstract
ObjectivesBipolar disorder (BD) is a highly heritable disorder with polygenic inheritance. Among the most consistent findings from functional magnetic imaging (fMRI) studies are limbic hyperactivation and dorsal hypoactivation. However, the relation between reported brain functional abnormalities and underlying genetic risk remains elusive. This is the first cross-sectional study applying a whole-brain explorative approach to investigate potential influence of BD case-control status and polygenic risk on brain activation.MethodsA BD polygenic risk score (PGRS) was estimated from the Psychiatric Genomics Consortium BD case-control study, and assigned to each individual in our independent sample (N=85 BD cases and 121 healthy controls (HC)), all of whom participated in an fMRI emotional faces matching paradigm. Potential differences in BOLD response across diagnostic groups were explored at whole-brain level in addition to amygdala as a region of interest. Putative effects of BD PGRS on brain activation were also investigated.ResultsAt whole-brain level, BD cases presented with significantly lower cuneus/precuneus activation than HC during negative face processing (Z-threshold=2.3 as cluster-level correction). The PGRS was associated positively with increased right inferior frontal gyrus (rIFG) activation during negative face processing. For amygdala activation, there were no correlations with diagnostic status or PGRS.ConclusionsThese findings are in line with previous reports of reduced precuneus and altered rIFG activation in BD. While these results demonstrate the ability of PGRS to reveal underlying genetic risk of altered brain activation in BD, the lack of convergence of effects at diagnostic and PGRS level suggests that this relation is a complex one.
Highlights
Bipolar disorder (BD) is a highly heritable disorder with polygenic inheritance
A BD polygenic risk score (PGRS) was estimated from the Psychiatric Genomics Consortium BD case-control study, and assigned to each individual in our independent sample (N=85 BD cases and 121 healthy controls (HC)), all of whom participated in an functional magnetic resonance imaging (fMRI) emotional faces matching paradigm
At whole-brain level, BD cases presented with significantly lower cuneus/precuneus activation than HC during negative face processing (Z-threshold=2.3 as cluster-level correction)
Summary
Bipolar disorder (BD) is a highly heritable disorder with polygenic inheritance. Large, recent studies with high statistical power have identified several genetic risk variants, most notably single nucleotide polymorphisms (SNPs) in calcium channel encoding genes [1].In comparison, functional magnetic resonance imaging (fMRI) studies of BD have yielded inconsistent results, likely partly due to low statistical power [2]. Recent studies with high statistical power have identified several genetic risk variants, most notably single nucleotide polymorphisms (SNPs) in calcium channel encoding genes [1]. A recent quantitative meta-analysis combining results from 65 fMRI studies (N = 1040 BD cases and 1074 healthy controls) found underactivation in the inferior frontal cortex and overactivation in limbic areas in BD patients relative to controls across emotional paradigms [4]. One of the most studied BD risk variants in fMRI analyses is the allele A in the CACNA1C SNP rs1006737, which has been related to increased amygdala activity during emotional paradigms, both in healthy controls (HC) [5], BD patients [6] and healthy relatives of BD patients [7]. The genome-wide association study (GWAS) approach has been applied to fMRI studies, of which one implicated a variant near a monoaminergic pathway gene (PHOX2B) in amygdala activity during a negative faces matching paradigm [9] in a sample of HC and patients
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