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

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

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J Psychiatry Neurosci 2014; 39(1): 31-9

Clifford Cassidy, MS; Lisa Buchy, PhD; Michael Bodnar, PhD; Jennifer Dell’Elce, BS; Zia Choudhry, MD; Ferid Fathalli, MD; Sarojini Sengupta, PhD; Rebecca Fox, BS; Ashok Malla, MD; Martin Lepage, PhD; Srividya Iyer, PhD; Ridha Joober, MD, PhD

Cassidy, Buchy, Bodnar, Dell’Elce, Chouldhry, Fathalli, Sengupta, Fox, Malla, Lepage, Iyer, Joober — Douglas Mental Health University Institute, Montréal, Que.; Malla, Lepage, Joober — Department of Psychiatry, McGill University, Montréal, Que., Canada


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 voxelbased 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.

Submitted Nov. 29, 2012; Revised Mar. 14, Apr. 23, 2013; Accepted Apr. 29, 2013.

Acknowledgements: We acknowledge the contributions of Dr. Mallar Chakravarty, Dr. Norbert Schmitz and Dr. Aurelie Labbé for statis tical advice and Aldanie Rho, Anastasia Lezos and Connie Lee for assistance with sample collection. This work was supported by grants from the Canadian Institutes of Health Research to A. Malla, M. Lepage and R. Joober. R. Joober has salary support from Fonds de la recherche en santé du Québec. The funding sources had no role in the design or conduct of the study, nor in the collection, interpretation of data, nor in the preparation, review, or approval of the manuscript.

Competing interests: None declared.

Contributors: A. Malla, M. Lepage and R. Joober designed the study. C. Cassidy, M. Bodnar, J. Dell’Elce, F. Ferid, R. Fox, S. Iyer and R. Joober acquired the data, which C. Cassidy, L. Buchy, M. Bodnar, J. Dell’Elce, Z. Choudhry, S. Sengupta, R. Fox, A. Malla, M. Lepage and R. Joober analyzed. C. Cassidy, M. Bodnar, J. Dell’Elce, R. Fox, S. Iyer and R. Joober wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.120242

Correspondence to: R. Joober, Douglas Mental Health University Institute, 6875 LaSalle Blvd., Montréal QC Canada H4H 1R3;