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Effects of a novel schizophrenia risk variant rs7914558 at CNNM2 on brain structure and attributional style

  • Emma Jane Rose (a1), April Hargreaves (a2), Derek Morris (a2), Ciara Fahey (a2), Daniela Tropea (a2), Elizabeth Cummings (a3), Carlo Caltagirone (a3), Paola Bossú (a4), Chiara Chiapponi (a4), Fabrizio Piras (a4), Gianfranco Spalletta (a4), Michael Gill (a5), Aiden Corvin (a5) and Gary Donohoe (a6)...

A single nucleotide polymorphism (rs7914558) within the cyclin M2 (CNNM2) gene was recently identified as a common risk variant for schizophrenia. The mechanism by which CNNM2 confers risk is unknown.


To determine the impact of the rs7914558 risk ‘A’ allele on measures of neurocognition, social cognition and brain structure.


Patients with schizophrenia (n = 400) and healthy controls (n = 160) completed measures of neuropsychological function and social cognition. Structural magnetic resonance imaging data were also acquired from an overlapping sample of Irish healthy controls (n = 159) and an independent sample of Italian patients (n = 82) and healthy controls (n = 39).


No effects of genotype on neuropsychological test performance were observed. However, a dosage effect of the risk allele was found for an index of social cognition (i.e. attributional style), such that risk status was associated with reduced self-serving bias across groups (GG>AG>AA, P<0.05). Using voxel-based morphometry to investigate neuroanatomical regions putatively supporting social cognition, risk carriers had relatively increased grey matter volume in the right temporal pole and right anterior cingulate cortex (P corrected<0.05) in the Irish healthy controls sample; neuroanatomical associations between CNNM2 and grey matter volume in anterior cingulate cortex were also observed in the Italian schizophrenia and healthy controls samples.


Although the biological role of CNNM2 in schizophrenia remains unknown, these data suggest that this CNNM2 risk variant rs7914558 may have an impact on neural systems relevant to social cognition. How such effects may mediate the relationship between genotype and disease risk remains to be established.

Corresponding author
Gary Donohoe, School of Psyhology, National University of Ireland, Galway, Ireland. Email:
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The Science Foundation Ireland, the Health Research Board (Ireland) and the Italian Ministry of Health provided financial support for these studies.

Declaration of interest


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Effects of a novel schizophrenia risk variant rs7914558 at CNNM2 on brain structure and attributional style

  • Emma Jane Rose (a1), April Hargreaves (a2), Derek Morris (a2), Ciara Fahey (a2), Daniela Tropea (a2), Elizabeth Cummings (a3), Carlo Caltagirone (a3), Paola Bossú (a4), Chiara Chiapponi (a4), Fabrizio Piras (a4), Gianfranco Spalletta (a4), Michael Gill (a5), Aiden Corvin (a5) and Gary Donohoe (a6)...
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Influences of schizophrenia risk variant rs7914558 at CNNM2 on brain structure

Kazutaka Ohi, M.D., Ph.D.
05 December 2014

Genome-wide significant variant at rs7914558, which is located in intron of the cyclin M2 (CNNM2) gene on chromosome 10q24.32, has been identified in a mega-analysis of genome-wide association studies (GWAS) inthe Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC).1 Recently, the largest GWAS combined all available schizophrenia samples in the PGC has identified genomic locus, including the CNNM2 gene,where genetic variant at rs11191419 (r2=0.608) was the most significant.2 Major alleles of both variants were related to risk for schizophrenia (Major 'G' allele at rs7914558 was risk). Using Irish and Italian cohorts of patients with schizophrenia and healthy controls, Rose et al. examined the relationships between the genome-wide significant variant at rs7914558and neurocognitions, cognitive functions and brain structures.3 They reported that the CNNM2 risk 'A' variant was associated with reduced self-serving bias in Irish 256 patients and 131 controls. In addition, they found the risk 'A' allele was associated with gray matter (GM) volumes in putative social cognition-related regions, such as the temporal pole and anterior cingulate cortex. The 'A' allele carriers had greater GM volumes in the right temporal pole and anterior cingulate cortex in 159 Irish healthy controls, reduced GM volumes in the left anterior cingulate cortexin Italian 66 patients with schizophrenia and greater GM volumes in the left anterior cingulate cortex in Italian 37 controls. In terms of providing evidence that the CNNM2 variant would contribute to social cognition and its neural underpinnings, it is very interesting study. However, the study has a very important limitation. Their reported risk allele was incorrect; i.e. the risk allele at rs7914558 is not minor 'A' but major 'G'. Therefore, interpretation of these associations was opposite. At nearly the same time, we have reported that the rs7914558 variant was associated with GM volumes in the orbital region of the bilateral inferiorfrontal gyri in Japanese 173 patients with schizophrenia and 449 healthy subjects.4 Individuals with the risk G/G genotype of rs7914558 had reducedGM volumes in the bilateral inferior frontal gyri than carriers of the non-risk A-allele. Interestingly, the orbital region of the inferior frontal gyrus plays also important role in social functions. Taken together, the variant was associated with reduced GM volumes in putative social cognition-related regions including the temporal pole, anterior cingulate and inferior frontal cortices that were reduced in patients with schizophrenia, although the detailed regions were not consistent among ethnics. Furthermore, recent study has indicated that mutations in the CNNM2 were associated with mental retardation and knockdown of cnnm2 isoforms in zebrafish showed disturbed brain development.5 These findings suggest that the CNNM2 variant may play a role in the social cognition andsocial functioning impairments noted in patients with schizophrenia through the volumetric vulnerability of these GM regions.

References1.Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011; 43: 969-976.2.Ripke S, Neale BM, Corvin A, Walters JT, Farh KH, Holmans PA, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature2014; 511: 421-427.3.Rose EJ, Hargreaves A, Morris D, Fahey C, Tropea D, Cummings E, et al. Effects of a novel schizophrenia risk variant rs7914558 at CNNM2 on brain structure and attributional style. Br J Psychiatry 2014; 204: 115-121.4.Ohi K, Hashimoto R, Yamamori H, Yasuda Y, Fujimoto M, Umeda-Yano S, et al. The impact of the genome-wide supported variant in the cyclin M2 gene on gray matter morphology in schizophrenia. Behav Brain Funct 2013; 9: 40.5.Arjona FJ, de Baaij JH, Schlingmann KP, Lameris AL, van Wijk E, Flik G,et al. CNNM2 mutations cause impaired brain development and seizures in patients with hypomagnesemia. PLoS Genet 2014; 10: e1004267.

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