We were also secondarily interested in integrating studies of genetic regulation of DNA methylation and of transcriptional expression, on a genome-wide scale, into a coherent framework for characterizing the underlying biological relevance of disease susceptibility loci. We found that of the most significant associations with Bipolar Disorder, SNPs that control both methylation and the expression of the same proximal gene are a small minority. This is consistent with a recent report that concludes that mQTLs and eQTLs largely capture independent traits 25. This finding lends substantial support to our thesis that, within the context of studies of brain pathophysiology, genetic variation controlling gene expression and genetic regulation of methylation present largely independent sources of variability in disease susceptibility. While a SNP may regulate both methylation and gene expression in brain, it is likely to do so with different target genes. DNA methylation may contribute to disease risk other than through influencing gene expression, for example by affecting DNA stability. Alternatively, methylation effects on expression may be more difficult to detect due to methodological limitations; for example, RNA is much more susceptible to degradation than DNA.
