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A Genome-Wide Linkage Scan for Age at Menarche in Three Populations of European Descent

Genetic Epidemiology and Molecular Epidemiology Laboratories (C.A.A., G.Z., S.A.T., N.G.M., P.M.V., G.W.M.), Queensland Institute of Medical Research, Brisbane, Queensland, Australia 4029; Twin Research and Genetic Epidemiology Unit (M.F., T.D.S.), St. Thomas’ Hospital, Kings College, London, United Kingdom SE1 7EH; Department of Biological Psychology (S.M.v.d.B., D.I.B.), Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; Department of Veterinary Medicine (S.M.v.d.B.), Utrecht University, 3508 GA Utrecht, The Netherlands; Institute of Evolutionary Biology (C.A.A.), School of Biological Sciences, University of Edinburgh, Edinburgh, Scotland EH9 3JT, United Kingdom; and Bioinformatics and Statistical Genetics (C.A.A.), Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom OX3 7BN

Address all correspondence and requests for reprints to: Grant W. Montgomery, Molecular Epidemiology Laboratory, Queensland Institute of Medical Research, Post Office, Royal Brisbane Hospital, Queensland 4029, Australia. E-mail: grant.montgomery{at}qimr.edu.au.

Context: Age at menarche (AAM) is an important trait both biologically and socially, a clearly defined event in female pubertal development, and has been associated with many clinically significant phenotypes.

Objective: The objective of the study was to identify genetic loci influencing variation in AAM in large population-based samples from three countries.

Design/Participants: Recalled AAM data were collected from 13,697 individuals and 4,899 pseudoindependent sister-pairs from three different populations (Australia, The Netherlands, and the United Kingdom) by mailed questionnaire or interview. Genome-wide variance components linkage analysis was implemented on each sample individually and in combination.

Results: The mean, SD, and heritability of AAM across the three samples was 13.1 yr, 1.5 yr, and 0.69, respectively. No loci were detected that reached genome-wide significance in the combined analysis, but a suggestive locus was detected on chromosome 12 (logarithm of the odds = 2.0). Three loci of suggestive significance were seen in the U.K. sample on chromosomes 1, 4, and 18 (logarithm of the odds = 2.4, 2.2 and 3.2, respectively).

Conclusions: There was no evidence for common highly penetrant variants influencing AAM. Linkage and association suggest that one trait locus for AAM is located on chromosome 12, but further studies are required to replicate these results.