A schizophrenia risk gene, ZNF804A, influences neuroanatomical and neurocognitive phenotypes

ZNF804A is one of the strongest candidate genes for schizophrenia (SZ), yet its function and role in disease pathophysiology are largely unknown. The only in vivo endophenotype study of the SZ-associated SNP (rs1344706) pointed towards effects on brain functional connectivity. We examined the relationship of this SNP to neuroanatomical and neurocognitive phenotypes that were assessed in healthy individuals. Volunteers with no history of psychiatric illness were assessed with structural magnetic resonance imaging (1.5T GE scanner, standard gradient-echo acquisition). Carriers of the minor allele were compared with homozygotes for the T (SZ-associated) allele on measures of total volume of the white matter (WM), gray matter (GM), and cerebrospinal fluid compartments, as well as on voxel-wise measurements of regional brain volumes. After examining the correlation between genotype-associated regions of interest and neurocognitive performance measures, the effects of rs1344706 genotype on a measure of visuomotor performance speed (trails A) were examined in an independent cohort of volunteers. Among healthy subjects, risk allele homozygotes showed larger total WM volumes than carriers of the other allele. Controlling for WM volumes, these same subjects showed reduced GM volumes in several regions comprising the 'default mode network,' including angular gyrus, parahippocampal gyrus, posterior cingulate, and medial orbitofrontal gyrus/gyrus rectus (FDR-corrected p<0.05). The risk allele dosage also predicted impairments on a timed visuomotor performance task (trails A). Results support a role of ZNF804A in phenotypes reflecting altered neural connectivity.