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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

Department of Endocrinology and Unit for Osteoporosis and Metabolic Bone Diseases (J.-M.K., I.V.P., K.T.), Ghent University Hospital, 9000 Ghent, Belgium; Institut National de la Santé et de la Recherche Médicale Unit 606 (A.O., M.C.-S., M.-C.d.V.), 75475 Paris, France; Institut National de la Santé et de la Recherche Médicale Unit 563 (A.S.-P., M.M.), 31024 Toulouse, France; Centre National de Génotypage (A.B.), 91057 Evry, France; and Department of Endocrinology (I.V.P.), Onze-Lieve Vrouwziekenhuis Ziekenhuis Aalst, 9300 Aalst, Belgium

Address all correspondence and requests for reprints to: Dr. Maria Martinez, Ph.D., Institut National de la Santé et de la Recherche Médicale Unit 563, Hôpital Purpan, BP 31024 Toulouse, France. E-mail: maria.martinez{at}toulouse.inserm.fr.

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

Objective: The objective of the study was to localize genes contributing to bone mineral density (BMD) variation.

Design: An autosomal genome-wide scan for BMD at the lumbar spine and femoral neck was conducted with variance components linkage methods.

Participants: A total of 103 pedigrees (Network in Europe on Male Osteoporosis Family Study) ascertained through a male relative with low (Z-score –2) BMD values at either lumbar spine or femoral neck.

Main Outcome Measures: Nonparametric multipoint logarithm of the odds ratio scores for lumbar spine and femoral neck BMD values adjusted for age, gender, and body mass index.

Results: We identified a total of eight chromosomal regions with logarithm of the odds ratio score of 1.5 or greater (P 5 x 10^–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 2 x 10^–5) or suggestive (11q12–13, 22q11, and 13q12–14, P 7 x 10^–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 linkage disequilibrium mapping is thus warranted.