A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations

Abstract

The gene MECP2 is a well-known determinant of brain structure. Mutations in the MECP2 protein cause microencephalopathy and are associated with several neurodevelopmental disorders that affect both brain morphology and cognition. Although mutations in MECP2 result in severe neurological phenotypes, the effect of common variation in this genetic region is unknown. We find that common sequence variations in a region in and around MECP2 show association with structural brain size measures in 2 independent cohorts, a discovery sample from the Thematic Organized Psychosis research group, and a replication sample from the Alzheimer's Disease Neuroimaging Initiative. The most statistically significant replicated association (P < 0.025 in both cohorts) involved the minor allele of SNP rs2239464 with reduced cortical surface area, and the finding was specific to male gender in both populations. Variations in the MECP2 region were associated with cortical surface area but not cortical thickness. Secondary analysis showed that this allele was also associated with reduced surface area in specific cortical regions (cuneus, fusiform gyrus, pars triangularis) in both populations.

Fig. 1.

Linkage disequilibrium map and −log of permuted and multiple comparison-corrected p-values for SNP dose vs. CA of MECP2 “expression module” (28) using data from 289 subjects from the TOP cohort.

Fig. 2.

Association of MECP2 SNP rs2239464 with cortical surface area in males in the TOP cohort. The map shows the distribution of nominal −log p-values (sign indicating direction of effect per copy of minor allele) across the reconstructed cortical surface. (Top) Lateral views. (Bottom) Mesial views. The corresponding map for females showed no significant effects (Fig. S1).