MECP2 Is Associated with Autism

Background: Autism is a neurodevelopmental disorder that affects approximately 1 in 150 individuals and is characterized by deficits in reciprocal social interaction, communication and patterns of repetitive behaviors and restricted interests. Twin and family studies indicate high heritability, but evidence supports a highly complex architecture for the underlying genetic etiology. Mutations in MECP2 give rise to Rett syndrome, which is classified as a PDD and shows many features of autism. Objectives: The objectives of this study were to test the hypothesis that common and/or rare alleles at MECP2 contribute to autism susceptibility. Methods: Using Hapmap Phase 2 data and the Tagger implementation in Haploview, we selected tag SNPs to index common alleles of the X-linked MECP2 locus. Five SNPs were genotyped in a sample of 965 combined simplex and multiplex families ascertained for idiopathic autism. FBAT and x-APL were used to test for over-transmission to affected offspring. Ancestry classification of founders was conducted using STRUCTURE and Multidimensional Scaling (MDS) implemented in PLINK, and where necessary supplemented with self report. Exons were re-sequenced in 200 unrelated cases and 200 unrelated controls using ABI Sanger chemistry to identify rare variants. Results: For three correlated tag SNPs selected for association analysis using Caucasian HapMap data, very different allele frequencies were apparent in other HapMap populations. Initial Hardy-Weinberg calculations during QC of genotype data revealed significant deviations from HWE. Ancestry was determined using a combination of STRUCTURE and MDS analyses supplemented with self report as needed. No deviations from HWE were found within individual ethnic groups; a significant majority of the sample was of European ancestry. Significant association (e.g. 0.005 > P (x-APL) > 0.0005) was identified at these three SNPs, corresponding to an LD block containing the 3' end of the gene. This association was restricted to families of European and Hispanic ancestries, although it is likely that power to detect transmission distortion in Asian and African-American families was very limited as a function of allele frequency. Sequencing in cases and controls did not reveal evidence for a greater mutation burden in cases. However, we did identify one family in which a mother transmitted an in-frame 3bp deletion to her affected son. Conclusions: We found significant association to autism at the 3' LD block of MECP2 in families of European and Hispanic ancestry. During the course of this work, evidence for association was published (Loat et al, 2008). The SNPs reported here are in strong LD with those in Loat et al, effectively replicating that finding. We also define important population effects that impact this association. These data support a role for MECP2 in idiopathic autism attributable to common alleles. While a potentially deleterious amino acid deletion was identified, comparison of sequencing results between cases and controls reported here does not support a major role for rare variants at this time. However, further studies of rare variation at MECP2 are needed.