The LEP gene and age of menarche: maternal age as a potential cause of hidden stratification in association studies.
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, <208/<208 bp, heterozygotes, and > or =208/> or =208 bp. A hierarchical ANOVA was performed with age of menarche as the dependent variable and 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) x 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 <30 years compared to those with a maternal age of > or =30 years. If maternal age effects prove to be generalized, failure to take them into consideration could provide a source of hidden stratification that could significantly alter the replication of association studies.
Comings
D E
DE
Department of Medical Genetics, City of Hope National Medical Center, Duarte, California 91910, USA.
Gade
R
R
Muhleman
D
D
Peters
W R
WR
MacMurray
J P
JP
D000328:Adult; D000367:Age Factors; D000483:Alleles; D000704:Analysis of Variance; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D020738:Leptin / Q000235:genetics*; D008423:Maternal Age; D008572:Menarche; D018895:Microsatellite Repeats; D015233:Models, Statistical; D009765:Obesity / Q000235:genetics; D011110:Polymorphism, Genetic
D020738:Leptin