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Human Molecular Genetics Advance Access published online on March 3, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi088
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© The Author 2005. Published by Oxford University Press. All rights reserved

Article

Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study

Stuart H Ralston 1*, Nick Galwey 2, Ian MacKay 2, Omar M E Albagha 3, Lon Cardon 4, Juliet E Compston 5, Cyrus Cooper 6, Emma Duncan 7, Richard Keen 8, Bente Langdahl 9, Alastair McLellan 10, Jeffrey O'Riordan 8, Huibert A Pols 11, David M Reid 3, Andre G Uitterlinden 11, John Wass 7, and Simon T Bennett 2

1 Rheumatic Diseases Unit, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK
2 Oxagen Ltd, 91 Milton Park, Abingdon OX14 4RY, UK
3 Bone Research Group, Institute of Medical Sciences, University of Aberdeen Medical School; Aberdeen AB25 2ZD, UK
4 Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN UK
5 University of Cambridge School of Clinical Medicine, Cambridge CB2 2QQ, UK
6 MRC Environmental Epidemiology Unit, Southampton General Hospital, Southampton SO16 6YD, UK
7 Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, The Churchill Hospital, Oxford, UK
8 University College London, HA4 4LP, UK
9 Department of Endocrinology, Århus Amtssygehus, Århus, Denmark
10 Department of Medicine & Therapeutics, Western Infirmary, Glasgow G11 6NT, UK
11 Department of Internal Medicine, Erasmus Medical Centre, P.O. Box 1738, 3000DR Rotterdam, The Netherlands

* To whom correspondence should be addressed.
Stuart H Ralston, E-mail: stuart.ralston{at}ed.ac.uk


  Abstract

Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mass and an increased risk of fracture. Bone mineral density (BMD) is a highly heritable trait and a key determinant of osteoporotic fracture risk, but the genes responsible are incompletely defined. Here we identified quantitative trait loci (QTL) for regulation of BMD by a genome-wide scan involving 3658 individuals from 715 families who were selected because of reduced BMD values at the lumbar spine (LS-BMD) or femoral neck (FN-BMD) in probands. Linkage analysis was conducted in the study group as a whole with correction for age, gender, weight and height. Further analyses were conducted for men and women separately to identify gender-specific QTL and for those under and over the age of 50 years, to distinguish QTL for peak bone mass from those that influence bone mass in older people. No regions of suggestive or significant linkage were identified when data from all subjects were analysed together. On subgroup analysis however, we identified a significant QTL for FN-BMD on chromosome 10q21 in men ≤50 years (lodscore +4.42) and two suggestive QTL for LS-BMD on chromosomes 18p11 (lodscore +2.83; women >50 years) and 20q13 (lodscore +3.20; women ≤50 years). We identified five other QTL for BMD with lodscores of greater than +2.20 on chromosomes 3q25, 4q25, 7p14, 16p13, and 16q23. This study provides evidence for gender-specific, site-specific and age-specific QTL that regulate BMD in humans and illustrates the importance of conducting subgroup analysis to detect these loci.


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