Meta-Analysis of Genome-Wide Scans Provides Evidence for Sex- and Site-Specific Regulation of Bone Mass

Abstract

Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner.Introduction: BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. Materials and Methods: Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. Results: For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p ‫ס‬ 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24. 31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p ‫ס‬ 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct.

Genetic influences on bone loss in the San Antonio Family Osteoporosis study

“…Many whole genome linkage scans have also been performed, with QTLs reported at a number of chromosomal regions, though specific QTLs have rarely been replicated across studies [5][6][7]28,[31][32][33][34][35][36], probably due, in part, to genetic heterogeneity among the populations studied. Analyses of BMD data from these previous studies, however, cannot adequately distinguish between loci affecting loss of BMD with age and those affecting the acquisition of peak bone mass occurring in young adulthood.…”

Polymorphisms in inflammation associated genes ALOX15 and IL-6 are associated with bone properties in young women and fracture in elderly

“…This region, which was also identified in an early meta--analysis of genome wide association studies (GWAS) for femoral neck BMD [10], includes the genes encoding arachidonate 12--lipoxygenase (ALOX12) and arachidonate 15--lipoxygenase (ALOX15). Lipid metabolites are produced from the polyunsaturated arachidonic acid [11], some of which have pro--inflammatory effects [12] and have been suggested to play role in chronic inflammation [13].…”

Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish

“…Our suggestive linkage at 14q23 to NN_Z was found for men but previously was found for BMD for men and women age 50 years and under [4]. The paucity of confirmatory linkages among studies may reflect the relatively low power in individual studies, differences in study design or genetic heterogeneity [34].…”