Objectives: The purpose of this study was to investigate the association of the six genes in the ERK pathway, including ERK2, MNK1, eIF4E1, 4EBP2, as well as the upstream regulators GRIN2A encoding NMDA receptor 2A and GRM1encoding mGluR1 with autism in an Iranian autism sample.
Methods: Family-based association analysis was performed using 700 individuals from 200 nuclear families from Iran with at least one autistic child. In total, 175 SNPs were genotyped for all six genes using Sequenom iPLEX. TDT analyses were performed with Plink software. TDT analyses were performed with Plink software. Quality control procedures applied to the data included rejection of any SNP markers with missingness greater than 0.15, MAF less than 0.01, HWE p-value less than 2.8*10-4, and Mendelian Error rate of greater than 0.1. Families with a Mendelian Error rate of greater than 0.05 were also removed. After QC, 150 SNPs and 672 individuals from 194 nuclear families were analyzed.
Results: We failed to identify a significant association with these six genes and ASD. The best result was a nominally significant association of two markers from GRM1 (rs9403771, p=.047, and rs2024589, p=.049) and one marker from GRIN2A (rs11645219, p=.046). Analysis is ongoing using Plink and FBAT to explore potential multimarker associations and gender effects.
Conclusions: Although the sample size for this investigation is small and slightly underpowered (For a significance level of 0.05, there is 78% power to detect a heterozygote GRR of 2.0 at D’ = 0.8 for q = 0.1), our results do not support the involvement of these genes in conferring risk for ASD.