Content area
Full Text
Letters to the Editor
1056
Inammatory and immune response genes have signicantly altered expression in schizophrenia
birth (hereafter the Developmental module). Functional annotation of this group of genes showed enrichment for nucleus, transcription regulation, chromatin regulator and chromatin modication (Figure 1b; Supplementary Table S2). The second module shows the opposite trend (Figure 1a), with a sharp increase in expression after birth (Adult module), with no signicant enrichment for any cellular process. To study the specicity of the enrichment of developmental genes, we used WGCNA to cluster again the disrupted genes, but this time together with genes that contained silent mutations. We then compared the distribution of disruptive vs silent mutations across the modules (Figure 1c). We found that genes with disruptive mutations were signicantly more likely to fall in the Developmental module compared with genes with silent mutations (P 0.0078, OR 2.0,
95% CI 1.23.4).
While it has been proposed that the origins of ASD are at the synapse, our meta-analysis of de novo mutations shows that many of the recently identied mutations are in genes that are involved in transcriptional regulation, specically chromatin-related proteins, which are active during brain development. Further evidence that lends support to the involvement of chromatin regulation in ASD is that three genes identied in this analysis (ARID1B, SMARCC2 and ADNP) are known to physically interact as a part of ATP-dependent chromatin remodeling complexes, which are essential during neural development.7 These ndings, together with the association of other genes in this category with autism and intellectual disability (for example, MLL3, MBD5),8 highlight the need to further study this class of genes as risk factors for ASD.
CONFLICT OF INTEREST
The authors declare no conict of interest.
ACKNOWLEDGEMENTS
This research was supported by a grant from the National Institute for Psychobiology in Israel.
E Ben-David and S Shifman Department of Genetics, The Institute of Life Sciences, The Hebrew
University of Jerusalem, Jerusalem, Israel E-mail: [email protected]
REFERENCES
1 Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J et al. De novo gene disruptions in children on the autistic spectrum. Neuron 2012; 74: 285299.
2 Neale BM, Kou Y, Liu L, Maayan A, Samocha KE, Sabo A et al. Patterns and rates of exonic de novo mutations in autism spectrum...