A Second-Stage Genome Scan for QTLs Influencing BMD Variation

Abstract

Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture. To identify genomic regions harboring quantitative trait loci (QTLs) contributing to BMD variation, we performed a two-stage genome screen. The first stage involved genotyping of a sample of 53 pedigrees with 630 individuals using 400 microsatellite markers spaced at approximately 10-cM intervals throughout the genome. Ten genomic regions with multi- and/or two-point LOD scores greater than 1.5 were observed. In the present second-stage study, 60 microsatellite markers, with a mean spacing of about 5 cM, were genotyped in these regions in an expanded sample of 79 pedigrees that contained 1816 subjects. Each pedigree was ascertained through a proband with extreme BMD at the hip or spine. BMD at the spine (L1-4), hip (the femoral neck, trochanter, and intertrochanteric region), and wrist (the ultradistal region) was measured by dual-energy X-ray absorptiometry (DXA) and was adjusted for age, sex, height, and weight. Two-point and multipoint linkage analyses were performed for each BMD site using statistical genetic methods that are implemented in the computer package SOLAR. Several regions (7q11, 10q26, 12q13, and 12q24) achieved LOD scores in excess of 1 in the second-stage followup study. The current results replicate some of our previous linkage findings and also highlight some of the difficulties facing microsatellite linkage mapping for complex human diseases.

Sex-Specific Genetic Loci for Femoral Neck Bone Mass and Strength Identified in Inbred COP and DA Rats

“…The corresponding human syntenic region on 5q31-35 and 17p11-13 were linked to neck BMD and axis length. (10,13) Sex-independent pleiotropic QTLs affecting both density and strength were found on Chr 1. Trabecular density QTL on Chr 1 was also linked to ultimate force ( Table 1).…”

“…Energy to break Female only D8Rat111-D8Rat15 3q21-24, Pelvic axis length (23) 11q22, Neck BMD (30) 15q22-25, Neck and hip BMD, neck cross-sectional area (18) Chr 10 Total vBMD All samples D10Rat162-D10Rat124 5q31-35, Neck BMD and axis length (13) Female only D10Rat162-D10Rat124 17p11-13, Neck and hip BMD (10) Cortical vBMD All samples D10Rat162-D10Rat124 Female only D10Rat162-D10Rat124 Ip All samples D10Rat162-D10Rat124 Total area…”

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.…”

Whole-Genome Scan for Linkage to Bone Strength and Structure in Inbred Fischer 344 and Lewis Rats

“…(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) Linkage studies in inbred mice have also provided linkage information for different bone phenotypes. (24)(25)(26)(27)(28)(29)(30)(31)(32)(33) Because the homologous regions of several animal models and human chromosomes are very well defined, it is possible to identify the chromosomal location of a gene accurately in humans by mapping it in animal models.…”