Bipolar disorder risk gene FOXO6 modulates negative symptoms in schizophrenia: a neuroimaging genetics study

Bipolar disorder risk gene FOXO6 modulates negative symptoms in schizophrenia: a neuroimaging genetics study


J Psychiatry Neurosci 2017;42(3):172-180

Joseph J. Shenker, MSc; Sarojini M. Sengupta, PhD; Ridha Joober, MD, PhD; Ashok Malla, MD; M. Mallar Chakravarty, PhD; Martin Lepage, PhD


Background: Despite being diagnostically associated uniquely with schizophrenia, negative symptoms are also observed in bipolar disorder (BD). Genome-wide association studies (GWAS) have uncovered a number of shared risk genes between schizophrenia and BD. The objectives of this study were to examine whether previously identified risk genes for BD are associated with negative symptom severity within a first-episode schizophrenia (FES) cohort and to examine whether such genes influence brain morphology.

Methods: Patients experiencing FES were genotyped for 21 previously identified BD risk genes; a series of univariate analyses of covariance examined the association between negative symptom severity, as measured using the Scale for the Assessment of Negative Symptoms (SANS), and genotype. A subset of participants underwent a structural 1.5 T MRI T1 scan, analyzed for surface area and cortical thickness changes via the CIVET pipeline and LPBA40 atlas.

Results: We included 133 patients with FES in our analysis; 61 of them underwent structural MRI. We observed a significant association between negative symptom severity and the BD risk gene FOXO6 (rs4660531). Individuals with the CC genotype presented significantly higher negative symptoms (Cohen d = 0.46, F = 5.854, p = 0.017) and significantly smaller surface area within the right middle orbitofrontal gyrus (Cohen d = 0.69, F = 7.289, p = 0.009) than carriers of allele A.

Limitations: Limitations of this study include its modest sample size and lack of a control sample.

Conclusion: Lacking the FOXO6 risk allele was associated with an increase in negative symptoms and surface area reduction in the right orbitofrontal gyrus — an area previously associated with negative symptoms — suggesting that presence of the FOXO6 risk allele confers resistance against negative symptoms and associated neuroanatomical changes in individuals with FES.

Submitted Oct. 15, 2015; Revised June 20, 2016; Accepted Aug. 31, 2016; Early-released Feb. 14, 2017

Acknowledgements: The authors thank Kathleen MacDonald and members of the Lepage and Chakravarty laboratories, notably Raihaan Patel and Gabriel Devenyi. The study was supported by operating grants from the Canadian Institutes of Health Research (CIHR; #68961) and the Sackler Foundation to M. Lepage, R. Joober and A. Malla. M. Chakravarty is supported by CIHR, the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Weston Brain Institute. Salary awards include Fonds de la Recherche en Santé du Québec (M. Lepage, R. Joober, M. Chakravarty), James McGill Professorship (M. Lepage) and Canada Research Chairs Program (A. Malla). The funding sources had no role in study design; the collection, analysis, or interpretation of data; the writing of the paper; or in the decision for publication.

Affiliations: From the Douglas Mental Health University Institute, Montreal, Que., Canada (Shenker, Sengupta, Joober, Malla, Chakravarty, Lepage); the Integrated Program in Neuroscience, McGill University, Montreal, Que., Canada (Shenker, Lepage); the Department of Psychiatry, McGill University, Montreal, Que., Canada (Sengupta, Joober, Malla, Chakravarty, Lepage); and the Department of Biomedical Engineering, McGill University, Montreal, Que., Canada (Chakravarty).

Competing interests: See for R. Joober. M. Lepage reports grants and personal fees from Otsuka Canada, Lundbeck and Janssen-Ortho, outside the submitted work. No other competing interests declared.

Contributors: R. Joober, M. Chakravarty and M. Lepage designed the study. S. Sengupta, R. Joober, A. Malla and M. Lepage acquired the data, which all authors analyzed. J. Shenker, A. Malla and M. Chakravarty wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.150332

Correspondence to: M. Lepage, Douglas Mental Health University Institute, Frank B Common Pavilion, F1143, 6875 LaSalle Blvd, Verdun, Quebec, Canada H4H 1R3;