First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q

Abstract

Osteoporosis is characterized by low bone density, and osteopenia is responsible for 1.5 million fractures in the United States annually. 1 In order to identify regions of the genome which are likely to contain genes predisposing to osteopenia, we genotyped 149 members of seven large pedigrees having recurrence of low bone mineral density (BMD) with 330 DNA markers spread throughout the autosomal genome. Linkage analysis for this quantitative trait was carried out using spine and hip BMD values by the classical lod-score method using a genetic model with parameters estimated from the seven families. In addition, non-parametric analysis was performed using the traditional Haseman-Elston approach in 74 independent sib pairs from the same pedigrees. The maximum lod score obtained by parametric analysis in all families combined was + 2.08 (θ = 0.05) for the marker CD3D on chromosome 11q. All other combined lod scores from the parametric analysis were less than + 1.90, the threshold for suggestive linkage. Non-parametric analysis suggested linkage of low BMD to chromosomes 1p36 (Z max = + 3.51 for D1S450) and 2p23-24 (Z max = + 2.07 for D2S149). Maximum multi-point lod scores for these regions were + 2.29 and + 2.25, respectively. A third region with associated lod scores above the threshold of suggestive linkage in both singlepoint and multi-point non-parametric analysis was on chromosome 4qter (Z max = + 2.95 for D4S1539 and Z max = + 2.48 for D4S1554). Our data suggest the existence of multiple genes involved in controlling spine and hip BMD, and indicate several candidate regions for further screening in this and other independent samples.

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].…”

“…For instance, the QTL region for femur Ip on Chr 1 is homologous to the region of human Chr 6q25-27, which is linked to spine and trochanter BMD [18]. Syntenic regions corresponding to the QTL regions for femur total area on Chrs 1, 6, 7 and 10 were also linked to wrist bone size on 9q21, forearm and hip BMD on 2p21-25, spine BMD on 22q13, and hip BMD on17p11-12 in humans [9,14,19]. Given the destructive nature of bone strength testing and the lack of statistical power in many human genome-wide linkage studies, it is not surprising that many QTL detected in this study have not been identified in human studies.…”

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

“…3,4 They included six multigenerational families, 28 nuclear families with two to four children and six three-generation families with two sibships of two to four offspring. Two families of two sisters each without parents that were included in a previous study 4 have been excluded from the present study because X-chromosome microsatellite marker genotypes were inconsistent with a sibling relationship.…”

“…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.…”

“…2 In 1998 we first reported a whole-genome scan of osteoporosis-related traits, based on the analysis of a small sample of extended Caucasian pedigrees of Canadian origin that had been selected through a proband with low bone mineral density (BMD). 3 Our study focused on quantitative trait linkage analysis of lumbar spine (LS) and femoral neck (FN) BMD and identified three regions with lod-scores X2.2 on chromosomes 1p, 2p, and 4q. 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.…”