Association of a risk allele of ANK3 with cognitive performance and cortical thickness in patients with first-episode psychosis

Abstract

Background: The gene ANK3 is implicated in bipolar disorder and schizophrenia. The present study investigated the influence of this gene on cognitive performance and brain structure among individuals with first-episode psychosis (FEP). The brief illness duration of an FEP sample makes it well suited for studying the effects of genetic variation.

Methods: We genotyped 2 single nucleotide polymorphisms (SNPs; rs1938526 and rs10994336) in ANK3 in patients with FEP. Multivariate analysis of variance compared risk allele carriers and noncarriers on 6 domains of cognition consistent with MATRICS consensus. A subsample of 82 patients was assessed using magnetic resonance imaging. We compared brain structure between carriers and noncarriers using cortical thickness analysis and voxel-based morphometry on white matter.

Results: In the 173 patients with FEP included in our study, rs1938526 and rs10994336 were in very high linkage disequilibrium (d' = 0.95), and analyses were therefore only carried out on the SNP (rs1938526) with the highest minor allele frequency (G). Allele G of rs1938526, was associated with lower cognitive performance across domains (F6,164 = 2.38, p = 0.030) and significantly lower scores on the domains of verbal memory (p = 0.015), working memory (p = 0.006) and attention (p = 0.019). The significant effects of this SNP on cognition were not maintained when controlling for IQ. Cortical thinning was observed in risk allele carriers at diverse sites across cortical lobes bilaterally at a threshold of p < 0.01, false discovery rate-corrected. Risk-allele carriers did not show any regions of reduced white matter volume.

Limitations: The sample size is modest given that a low-frequency variant was being examined.

Conclusion: The ANK3 risk allele rs1938526 appears to be associated with general cognitive impairment and widespread cortical thinning in patients with FEP.

Fig. 1

t Statistical maps of cortical thickness comparing carriers and noncarriers of the G allele at rs1938526. Negative values of the t statistic correspond to thinner cortex in rs1938526 risk (G) allele carriers. Carriers (n = 14) had a significantly thinner cortex than noncarriers (n = 68) at vertices shown in white at p < 0.01, false discovery rate (FDR)–corrected, and at vertices shown in violet at p < 0.05, FDR-corrected.