A Common MECP2 Haplotype Associates With Reduced Brain Size and Cortical Area in Humans

Abstract

Ole A Andreassen¹,Alexander H Joyner², Cooper S Roddey², Cinnamon S Bloss², Trygve E Bakken², Lars M Rimol¹, Ingrid Melle¹, Kjetil Sundet¹, Ingrid Agartz1^|, Srdjan Djurovic¹, Eric J Topol², Nicholas J Schork², Anders M Dale ²

MECP2 gene is located on Xq28 and encodes the methyl CpG binding protein 2. Mutation of this gene results in a wide range of neurodevelopmental disorders including Rett syndrome, autism, mental retardation, and mild learning disabilities. 

Structural brain images and genotype data were acquired from a cohort of healthy control and psychotic subjects (n=289), and variants in the disease-causing gene MECP2 were found to associate with reduced brain size and cortical area. The most statistically significant association involved reduced intracranial volume (p<.0008), and the finding was specific to male gender. It appears that females may be more robust to the effect of common genetic variations in MECP2.  Secondary analysis showed that subcortical structures with reduced volume were also associated with this allele.  Variation in MECP2 determines the area of cortex, but not its thickness. Dissection of the MECP2 network is likely to yield fundamental insights into brain development in both normal and disease cohorts.

¹Department of Psychiatry, Ullevål University Hospital and Institutes of Psychiatry and Psychology, University of Oslo, N-0407 Oslo, Norway, ²Scripps Translational Science Institute and UCSD Department of Neurosciences, La Jolla, CA 9209 USA