Maternal age at the birth of the first child as an epistatic factor in polygenic disorders

The identification of the genes for complex, polygenic disorders has proven difficult. This is due to the small effect size of each gene and genetic heterogeneity. An additional important factor could be the presence of unidentified epistatic factors. In the broad definition of epistasis, the effect of one unit is not predicable unless the value of another unit is known and one of the units may not be a gene. We have previously identified maternal age as an epistatic factor for the effect of the LEP gene on the age of onset of menarche. We report here the effect of maternal age and the age of the mother at the birth of her first child (maternal age 1st) as epistatic factors for the interaction of the dopamine D1 gene (DRD1) with obsessive-compulsive behaviors and with stuttering. The epistatic effects of maternal age 1st were stronger than maternal age. This type of epistatic factor may be generalizable to many other gene-trait interactions. (C) 2005 Wiley-Liss, Inc.