A genome-wide significant variant at rs7914558, which is located in the intron of the cyclin M2 gene (CNNM2) on chromosome 10q24.32, has been identified in a meta-analysis of genome-wide association studies (GWAS) by the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). ^{Reference Ripke, Sanders, Kendler, Levinson, Sklar and Holmans1} Recently, the largest GWAS, combining all available schizophrenia samples in the PGC, has identified genomic loci, including the CNNM2 gene where the genetic variant at rs11191419 (r ² = 0.608) was the most significant. ² Major alleles of both variants were related to risk for schizophrenia (the major G allele at rs7914558 was a risk allele).

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 rs7914558 and neurocognition, cognitive function and brain structure. ^{Reference Rose, Hargreaves, Morris, Fahey, Tropea and Cummings3} They reported that the CNNM2 risk A variant was associated with reduced self-serving bias in 256 Irish patients and 131 controls. In addition, they found the risk A allele was associated with grey matter volume in putative social cognition-related regions, such as the temporal pole and anterior cingulate cortex. The A-allele carriers had greater grey matter volume in the right temporal pole and anterior cingulate cortex in 159 Irish healthy controls, reduced grey matter volume in the left anterior cingulate cortex in 66 Italian patients with schizophrenia, and greater grey matter volume in the left anterior cingulate cortex in 37 Italian controls.

In terms of providing evidence that the CNNM2 variant would contribute to social cognition and its neural underpinnings, it is a very interesting study. However, the study has a very important limitation. The reported risk allele was incorrect: the risk allele at rs7914558 is not minor ‘A’ but major ‘G’. Therefore, interpretation of these associations was opposite.

At almost the same time, we reported that the rs7914558 variant was associated with grey matter volume in the orbital region of the bilateral inferior frontal gyri in 173 Japanese patients with schizophrenia and 449 healthy individuals. ^{Reference Ohi, Hashimoto, Yamamori, Yasuda, Fujimoto and Umeda-Yano4} Those with the risk G/G genotype of rs7914558 had reduced grey matter volume in the bilateral inferior frontal gyri compared with carriers of the non-risk A allele. Interestingly, the orbital region of the inferior frontal gyrus also plays an important role in social functioning. Taken together, the variant was associated with reduced grey matter volume in putative social cognition-related regions, including the temporal pole, anterior cingulate and inferior frontal cortices, which were reduced in patients with schizophrenia, although the detailed regions were not consistent among the different populations studied.

Furthermore, a recent study has indicated that mutations in the CNNM2 gene are associated with intellectual disability, and the knockdown of Cnnm2 isoforms in zebrafish has resulted in disturbed brain development. ^{Reference Arjona, de Baaij, Schlingmann, Lameris, van Wijk and Flik5} These findings suggest that the CNNM2 variant might play a role in the social cognition and social functioning impairments noted in patients with schizophrenia through the volumetric vulnerability of these grey matter regions.