Comparison of Genome Screens for Two Independent Cohorts Provides Replication of Suggestive Linkage of Bone Mineral Density to 3p21 and 1p36

Abstract

Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture. Studies of BMD in families and twins have shown that this trait is under strong genetic control. To identify regions of the genome that contain quantitative trait loci (QTL) for BMD, we performed independent genomewide screens, using two complementary study designs. We analyzed unselected nonidentical twin pairs (1,094 pedigrees) and highly selected, extremely discordant or concordant (EDAC) sib pairs (254 pedigrees). Nonparametric multipoint linkage (NPL) analyses were undertaken for lumbar spine and total-hip BMD in both cohorts and for whole-body BMD in the unselected twin pairs. The maximum evidence of linkage in the unselected twins (spine BMD, LOD 2.7) and the EDAC pedigrees (spine BMD, LOD 2.1) was observed at chromosome 3p21 (76 cM and 69 cM, respectively). These combined data indicate the presence, in this region, of a gene that regulates BMD. Furthermore, evidence of linkage in the twin cohort (whole-body BMD; LOD 2.4) at chromosome 1p36 (17 cM) supports previous findings of suggestive linkage to BMD in the region. Weaker evidence of linkage (LOD 1.0-2.3) in either cohort, but not both, indicates the locality of additional QTLs. These studies validate the use, in linkage analysis, of large cohorts of unselected twins phenotyped for multiple traits, and they highlight the importance of conducting genome scans in replicate populations as a prelude to positional cloning and gene discovery.

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

“…No evidence of linkage was detected at genome-wide significance; the greatest linkage signal was observed for 33% ulna ΔBMD with a LOD score of 1.90 at 81 cM on chromosome 3p (unadjusted p=0.0018). This region has previously been implicated in lumbar spine BMD in unselected twins and extremely discordant or concordant sib pairs [28]. A novel signal for hip ΔBMD with a LOD score of 1.75 at 103 cM on chromosome 6q was also observed (unadjusted p=0.0008).…”

“…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.…”

Genetic loci affecting bone structure and strength in inbred COP and DA rats

“…The sex-specific allelic effects for those QTL were clearly observed for genotypic mean values of these phenotypes. Interestingly, the syntenic region for female-specific work to failure in rat coincides with the whole body and hip BMD on 1p36 in human [13,14]. The male-specific QTL for L5 cortical area on Chr 2 share linkage homology with human chromosome 3q24-25 for pelvic axis length, midfemur, femur head and femur shaft width [15,16], as well as with chromosome 13q14 for trochanter BMD [17].…”

Univariate and bivariate variance component linkage analysis of a whole-genome scan for loci contributing to bone mineral density

“…Linkage of FN BMD to chromosome 1p36 was confirmed by highdensity mapping in an extended sample that included 36 additional families selected from the same population. 4 Since our initial study, several other groups have reported genome scans for bone-related traits (reviewed in Liu et al; 5 also more recently Kammerer et al, 6 Styrkarsdottir et al, 7 Wilson et al, 8 Huang et al, 9 Karasik et al, 10 and Shen et al 11 ). In spite of heterogeneity in sampling strategies, statistical approaches, traits, and populations, these studies have identified several common chromosomal regions that are candidates for loci responsible for susceptibility to osteoporosis.…”

“…12 Among these regions, chromosome 1p36, initially identified in our pedigrees 3,4 has been confirmed to contain a quantitative trait locus (QTL) for bone-related traits in several other studies. 8,13,14 As in the analysis of all complex traits, replication in independent studies is a key parameter in defining the significance of a linkage finding.…”