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.

ABSTRACT

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 < or = -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 < or = 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 < or = 2 x 10(-5)) or suggestive (11q12-13, 22q11, and 13q12-14, P < or = 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.