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Genomewide Linkage Scan for Quantitative Trait Loci Underlying Variation in Age at Menarche

Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi’an Jiaotong University (Y.G., T.-L.Y., H.-W.D.), Xi’an 710049, People’s Republic of China; Osteoporosis Research Center and Department of Biomedical Sciences, Creighton University (Y.G., P.X., D.-H.X., T.-L.Y., J.-R.L., R.R.R.), Omaha, Nebraska 68131; Department of Orthopedic Surgery, School of Medicine, University of Missouri-Kansas City (H.S., Y.-F.G., H.-W.D.), Kansas City, Missouri 64108; and Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University (Y.-F.G., H.-W.D.), Changsha, Hunan 410081, People’s Republic of China

Address all correspondence and requests for reprints to: Dr. Hong-Wen Deng, Department of Basic Medical Science, University of Missouri School of Medicine, Room M3-CO3, 2411 Holmes Street, Kansas City, Missouri 64108-2792. E-mail: dengh{at}umkc.edu.

Context: Age at menarche (AAM) is an important anthropological variable that has major implications for a woman’s health later in life. Genetic influence has been shown to contribute greatly to AAM, but the specific genetic determinants are largely unknown.

Objective: The objective of this study was to identify the quantitative trait loci (QTL) underlying the variations in AAM.

Methods: We performed a large-scale, genomewide, linkage scan in 2461 Caucasian women from 402 pedigrees. All subjects were genotyped with 410 microsatellite markers spaced approximately 8.9 cM apart across the human genome. Using the variance component method, we conducted multipoint linkage analyses and two-locus tests for epistatic interaction.

Results: The strongest linkage signal was obtained at the genomic region of 22q13 (LOD, 3.70); the other two suggestive linkages were on 22q11 (LOD, 2.68) and 11q23 (LOD, 1.98), respectively. We also detected significant epistatic interaction between genomic regions 22q13 and 3q13.

Conclusions: The identification of QTL and epistatic interaction in a large female sample laid a foundation for independent replication and fine-mapping studies as well as positional and functional candidate gene studies aimed at finding the causal genetic variants and hidden mechanisms concerning the variations in AAM.

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