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This version published online on July 29, 2008
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2008-0678
A more recent version of this article appeared on October 1, 2008
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Submitted on March 27, 2008
Accepted on July 23, 2008

Genome-wide linkage screen of bone mineral density (BMD) in European pedigrees ascertained through a male relative with low BMD values: Evidence for Quantitative Trait Loci on 17q21–23, 11q12–13, 13q12–14 and 22q11

Jean-Marc Kaufman, Agnès Ostertag, Aude Saint-Pierre, Martine Cohen-Solal, Anne Boland, Inge Van Pottelbergh, Kaatje Toye, Marie-Christine de Vernejoul, and Maria Martinez*

Department of Endocrinology & Unit for Osteoporosis and Metabolic Bone Diseases, Ghent University Hospital, Belgium (JMK, IVP, KT); INSERM U606, Paris, France (AO, MCS, MCdV); INSERM U563, Toulouse, France (ASP, MM); Centre National de Génotypage, Evry, France (AB); and Department of Endocrinology, OLV Ziekenhuis Aalst, Belgium (IVP)

* To whom correspondence should be addressed. E-mail: maria.martinez{at}toulouse.inserm.fr.

Context: Bone mass is under strong genetic control, with heritability estimates >50%, and is likely determined by complex interactions between genetic and environmental factors

Objective: To localize genes contributing to Bone Mineral Density variation.

Design: An autosomal genome-wide scan for BMD at the Lumbar Spine and at the Femoral Neck was conducted with variance components linkage methods.

Participants: 103 pedigrees (NEMO Family Study) ascertained through a male relative with low (Z-score ≤-2) BMD values at either Lumbar Spine or Femoral Neck.

Main outcome measures: Non-parametric multipoint LOD scores for Lumbar Spine and Femoral Neck BMD values adjusted for age, gender and BMI.

Results: We identified a total of 8 chromosomal regions with LOD score ≥1.5 (P≤5x10-3): on 1q42–43, 11q12–13, 12q23–24, 17q21–23, 21q22 and 22q11 for Lumbar Spine, and on 5q31–33 and 13q12–14 for Femoral Neck BMD.

Conclusions: Four of our detected Quantitative Trait Loci (QTL) reached the genome-wide criteria for "significant" (17q,21–23, P≤2x10-5) or "suggestive" (11q12–13, 22q11 and 13q12–14, P≤7x10-4) linkage. Apart from 22q11, which is a novel QTL, all other loci provide consistent replication for previously reported QTLs for BMD and other bone-related traits. Finally, several of our specific-linkage areas encompass prominent candidate genes: type 1 collagen (COL1A1) and the sclerosteosis/van Buchem disease (SOST) genes on 17q21–23; the low-density lipoprotein receptor-related protein 5 (LRP5) gene on 11q12–13, and the Rank Ligand gene on 13q12–14. Further analysis of these positive regions by fine LD-mapping is thus warranted.
Key words: BMD • osteoporosis • genome-wide scan • variance-component linkage






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