The LEP Gene and Age of Menarche: Maternal Age as a Potential Cause of Hidden Stratification in Association Studies

Abstract Leptin has a powerful effect on fertility and the initiation of puberty in addition to its effect on obesity. It has been suggested that that in times of fasting, infertility induced by low leptin levels protect the female from the energy demands of pregnancy. Despite this there have been no studies of the potential role of LEP gene variants on the age of onset of menarche. We genotyped 183 non-Hispanic Caucasian adult females at the LEP D7S1875 dinucleotide repeat polymorphism. The alleles were placed into three genotypes, LEP 1875 genotypes and maternal age (age of the mothers at birth of the subject) as independent variables. There was a significant ( P ≤ 0.006) interaction of LEP 1875 × maternal age but neither independent variable was significant by itself. This was due to an “association crossover effect” in which the LEP 1875 by age of menarche effects were in opposite directions for those with a maternal age of