Abstract
Schizophrenia (SCZ) and bipolar disorder (BD) have high heritability. Genome-wide association studies (GWAS) have identified ZNF804A as a significant risk gene for both illnesses. A validation of this finding at the brain systems-level is imperative as there is still little understanding of how it heightens risk. Based in part on our recent findings of an effect on widespread decreased white matter microstructural fractional anisotropy (putatively a proxy of its integrity), particularly strong in SCZ, we asked whether the risk allele has a detrimental effect on regional brain activation and functional connectivity during a type of cognitive processing which is, together with its neural correlates, impaired in BD and SCZ: verbal fluency. Functional MRI and genotype data was collected from 80 healthy volunteers, and 54 SCZ and 40 BD patients. A standard multifactorial analysis of variance using statistical parametric mapping and significance correction of FWE p < 0.05 was used. We found the GWAS risk allele A was associated with decreased positive functional coupling between the left precentral gyrus/inferior frontal gyrus (i.e. the most highly recruited area for the task) and: 1) the left inferior frontal gyrus, and 2) the left posterior cingulate gyrus, encompassing the precuneus; both as a main effect across controls and psychosis patients. Such association of the risk allele with reduced functional connectivity (with no area where the opposite main effect was detected), converges with findings in other tasks, our previous finding of its widespread impact on brain white matter microstructure, and with the dysconnectivity hypothesis of SCZ.
Highlights
Schizophrenia (SCZ) and bipolar disorder (BD) have high heritability
We genotyped and scanned, with functional MRI, 174 English native speakers [80 healthy volunteers without history of mental illness, 54 patients with SCZ and 40 with BD (75% of whom had a history of psychosis symptoms)], recruited from the SLAM National Health Service (NHS) Trust and diagnosed according to DSM-IV
We found a genotype-by-diagnosis interaction in the left inferior frontal gyrus, pars opercularis/triangularis [Z=4.39; whole-brain, voxel-wise FWE-corrected p=0.03; ηp2= 4.32%; Figure 1 - Part A], where risk allele A was associated with higher regional activation in BD, but the reverse was seen in healthy volunteers
Summary
Schizophrenia (SCZ) and bipolar disorder (BD) have high heritability. Genome-wide association studies (GWAS) have robustly identified ZNF804A as a significant risk gene for both illnesses (Gurung and Prata, 2015), by virtue of it containing the rs1344706 polymorphism for which the adenine (A) allele was slightly more common in both patient groups. We asked whether it would, have a detrimental effect (and possibly larger in SCZ patients) on regional brain activation and functional connectivity during a type of cognitive processing which is, together with its neural correlates, affected in BD and SCZ, and their healthy relatives (Curtis et al, 2001; Daban et al, 2006): verbal fluency (Prata et al, 2009) Such effect would be consistent with previous findings associating it with a decrease in functional connectivity during working memory (Esslinger et al, 2009; Rasetti, 2011). Effects seem smaller or less detectable, with one study showing a weak-to-modestly linked allele (in terms of linkage disequilibrium) to be marginally associated with better category fluency, but not verbal fluency, in healthy males (Nicodemus et al, 2014); and the present risk allele with worse visuo-motor performance, but again not verbal fluency nor verbal learning (Lencz et al, 2010)
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