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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 9 3116-3120
Copyright © 2000 by The Endocrine Society

Original Studies

Genome Screen for QTLs Contributing to Normal Variation in Bone Mineral Density and Osteoporosis1

D. L. Koller, M. J. Econs, P. A. Morin, J. C. Christian, S. L. Hui, P. Parry, M. E. Curran, L. A. Rodriguez, P. M. Conneally, G. Joslyn, M. Peacock, C. C. Johnston and T. Foroud

Indiana University School of Medicine (D.L.K., M.J.E., J.C.C., S.L.H., P.M.C., M.P., C.C.J., T.F.), Indianapolis, Indiana 46202; and Axys Pharmaceuticals, Inc. (P.A.M., P.P., M.E.C., L.A.R., G.J.), La Jolla, California 92037

Address all correspondence and requests for reprints to: Dr. Tatiana Foroud, Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 West Walnut Street, Indianapolis, Indiana 46202.


   Abstract
Top
 Abstract
Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 
A major determinant of the risk for osteoporosis is peak bone mineral density (BMD), which is largely determined by genetic factors. We recently reported linkage of peak BMD in a large sample of healthy sister pairs to chromosome 11q12–13. To identify additional loci underlying normal variations in peak BMD, we conducted an autosomal genome screen in 429 Caucasian sister pairs. Multipoint LOD scores were computed for BMD at four skeletal sites. Chromosomal regions with LOD scores above 1.85 were further pursued in an expanded sample of 595 sister pairs (464 Caucasians and 131 African-Americans).

The highest LOD score attained in the expanded sample was 3.86 at chromosome 1q21–23 with lumbar spine BMD. Chromosome 5q33–35 gave a LOD score of 2.23 with femoral neck BMD. At chromosome 6p11–12, the 464 Caucasian pairs achieved a LOD score of 2.13 with lumbar spine BMD. Markers within the 11q12–13 region continued to support linkage to femoral neck BMD, although the peak LOD score was decreased to 2.16 in the sample of 595 sibling pairs. Our study is the largest genome screen to date for genes underlying variations in peak BMD and represents an important step toward identifying genes contributing to osteoporosis in the general population.


   Introduction
Top
 Abstract
 Introduction
Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 
OSTEOPOROTIC fractures of the hip and spine are a major public health problem, occurring at a rate of over 1.3 million/yr in the United States and accounting for over $10 billion in healthcare expenses (1). Low bone mineral density (BMD) in later life is a major contributing factor to osteoporotic fractures. BMD reaches a peak in the third or fourth decade and declines with age in both sexes. Low BMD in later life results from low peak BMD, a high rate of bone loss, or a combination of both.

The role of genetic factors in the rate of bone loss is unclear (2, 3, 4). However, these data (5) as well as those reported by others (6, 7) have shown as much as 80% of the variability in peak BMD to be attributable to genetic factors. Gender and race are also important predictors of peak BMD, with men and African-Americans having higher average peak BMD than women and Caucasians, respectively (8). Several genes probably contribute and interact to produce variability in peak bone density. Identification of these genes will be important in understanding the underlying mechanisms of bone formation and maintenance and in providing molecular targets for future osteoporosis therapies.

To date, most efforts toward understanding the genetics of bone density have focused on population-based case-control association studies of candidate genes known to be involved in bone metabolism. These include the vitamin D receptor (9, 10, 11), the type I collagen {alpha}1 gene (12, 13), the estrogen receptor (14, 15), and interleukin-6 (16). Positive and negative association results have been reported for each of these candidate genes, and a significant role in BMD variability in the general population for any or all of these genes remains highly controversial (17). In a previous study we employed a candidate region approach (18) and found linkage of BMD in a sample of healthy premenopausal women to a candidate region at chromosome 11q12–13, of interest due to the mapping of several Mendelian bone density phenotypes to this region (19, 20, 21).

Genome-wide linkage screens for genes underlying BMD variability have been conducted in humans (22, 23) and mice (24, 25, 26). Devoto et al. (22) studied 7 extended pedigrees ascertained via probands with low BMD and reported linkage to chromosome regions 1p, 2p, and 4q. Niu et al. (23) measured radial BMD in 153 Chinese sibling pairs and reported linkage to chromosomes 2p and 13q. All of the mouse studies cited above found linkage to regions homologous to human chromosome 11q12–13 as well as other chromosomal regions. Identification of the genes underlying BMD variation in animal models will provide novel or known genes that can be evaluated for possible effects on BMD in humans.

We report a genome-wide linkage screen with BMD in 429 healthy Caucasian, premenopausal sister pairs, ascertained without regard to bone density. We also performed additional genotyping of a larger sample of Caucasian and African-American sister pairs for markers in the regions of interest (LOD >1.85) identified in the genome screen.


   Experimental Subjects
Top
 Abstract
 Introduction
 Experimental Subjects
Materials and Methods
 Results
 Discussion
 References
 
Full siblingships consisting of Caucasian and African-American healthy premenopausal women, aged 20–45 yr, were recruited in Indiana. Blood samples were obtained from all participating sisters and, whenever possible, from one of their parents. DNA was isolated using standard techniques (27). Informed, written consent (IRB 8502–23) was obtained from all participants.

BMD was measured by dual energy x-ray absorptiometry (DPXL, Lunar Corp., Madison, WI) at the lumbar (L2–L4) spine, trochanter, femoral neck, and Ward’s triangle. Sisters were measured on the same machine. Height and weight were obtained for each sister, along with oral contraceptive and smoking (pack-years) history. Stepwise regression analysis was employed using these four variables along with age to identify significant covariates (P < 0.05) with BMD. Race-specific regression residuals, representing covariate-adjusted BMD values, were computed and used in all subsequent analyses.


   Materials and Methods
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
Results
 Discussion
 References
 
Marker genotyping

A total of 270 markers were genotyped for 429 Caucasian sister pairs and 1 of their parents, where available. Markers were selected from the ABI/Prism genome screening set (ABI, Foster City, CA), with additional public markers selected to fill large intermarker gaps. The average spacing of the markers was 12.9 centimorgans (cM). All markers were highly informative dinucleotide or tetranucleotide repeat polymorphisms, with heterozygosity greater than 0.70. PCRs for each marker were performed separately, and products were combined before gel electrophoresis. Data were collected using 373A or 377 automated DNA sequencers and genotyped using the Genescan Analysis and Genotyper software (Perkin-Elmer Corp., Norwalk, CT). Genotypes were normalized to control for gel to gel size variation, binned, coded, and checked for Mendelian inheritance.

The marker genotype data were used to verify the full sibling relationships among the subjects using the computer programs RELATIVE (28) and RELPAIR (29). Half-sibling pairs, identified based on aberrant IBD allele sharing, were eliminated from further analyses.

Quantitative linkage analysis

Multipoint quantitative linkage analysis was performed for BMD at each skeletal site using the maximum likelihood variance components method as implemented in the computer package Mapmaker/SIBS (30). LOD scores were computed at 1-cM intervals along each autosome, using all possible sibling pairs formed from families larger than two sisters. Observed allele frequencies in the individuals genotyped for the genome screen were used. Marker order and map positions were obtained from the Marshfield electronic database (http://www.marshmed.org/genetics/).

Interesting linkage findings (LOD >1.85) in the initial genome screen sample of 429 Caucasian sister pairs were further pursued in an expanded sample of 464 Caucasian and 131 African-American sister pairs. Markers in these chromosomal regions of interest were selected for genotyping in the expanded sample. Due to the relatively small size of the African-American sample and the possibility of differences in effect of a particular QTL between racial groups, the Caucasians were analyzed both alone and jointly with the African-American sample for the follow-up analysis of interesting chromosomal regions. For the joint Caucasian/African-American analysis, race-specific allele frequencies were used by coding each marker allele differently for Caucasian and African-American individuals as described previously (18).


   Results
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
Discussion
 References
 
As expected, African-American participants had greater average BMD (8) at all skeletal sites (Table 1Go). The mean age was 33.9 yr, and the mean difference in age between sisters was 3.6 yr (Table 2Go). Of the covariates studied, only age and weight approached significance (P < 0.10) in stepwise model fitting. Residuals from race-specific regression model fitting were used as age- and weight-adjusted BMD values in all subsequent analyses.


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  		Table 1. BMD of sibling pair study participants

 

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  		Table 2. Genome screen participants (all Caucasian)

 
Multipoint linkage analysis of BMD at the four skeletal sites using Mapmaker/SIBS identified seven regions with LOD scores above 1.85 in the genome screen sample (Table 3Go). The maximum LOD score attained in the genome screen was 3.11, with spine BMD on chromosome 1q near marker D1S484. Six additional chromosomal regions (5q, 6p, 11q, 14q, and 22q) attained LOD scores above 1.85; however, only the linkage findings on chromosomes 1, 5, 6, 11, and 22 were at or near a marker locus. Among these chromosomal regions, only the 11q12–13 region had evidence for linkage to additional BMD measures with a LOD score above 1.0 in the genome screen (LOD = 1.67 with femoral neck BMD). The 11q region had already been pursued by genotyping all available samples (18), and therefore only four novel chromosomal regions (1q, 5q, 6p, and 22q) were further genotyped in the expanded sample of Caucasian and African-American sister pairs. Since the previous report of linkage to chromosome 11q12–13 (18), 84 additional Caucasian pairs had been ascertained and genotyped for the genome screen markers and for markers in the regions of interest on chromosomes 1, 5, 6, 11, and 22.


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  		Table 3. Genome screen results (LOD scores >1.85)

 
The multipoint LOD score for spine near D1S484 on chromosome 1q increased from 3.11 in the all-Caucasian genome screen sample to 3.64 in the expanded sample of Caucasians and 3.86 in the combined sample of Caucasian and African-American sister pairs (Table 4Go and Fig. 1Go). The LOD score for femoral neck on chromosome 5q also increased in the expanded samples, from an initial genome screen LOD score of 1.87 to a value of 2.03 in the expanded sample of Caucasians and to 2.23 in the combined sample of Caucasian and African-American pairs. In all three samples (genome screen, expanded Caucasian, and combined Caucasian and African-American), the maximum LOD score occurred near marker D5S422. Evidence for linkage of spine BMD to chromosome 6p also increased in the enlarged Caucasian sample, from a LOD score of 1.94 to 2.13 between markers D6S257 and D6S462. When African-Americans were included in the analysis, the LOD score decreased to 1.93 in the same location.


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  		Table 4. Expanded sample

 


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  		Figure 1. Multipoint linkage results (from Mapmaker/SIBS) with BMD for the chromosomal regions genotyped in the expanded sample of Caucasian and African-American sister pairs. Marker positions are indicated below the x-axis. The dashed line indicates linkage results for a Caucasian genome screen sample (n = 429 pairs), the thin line shows the results for an expanded Caucasian sample (n = 464 pairs), and the thick line shows the results for the combined sample of Caucasian and African-American sister pairs (n = 595 pairs). Results are shown for chromosome 1 lumbar spine BMD (A), chromosome 5 femoral neck BMD (B), chromosome 6 lumbar spine BMD (C), chromosome 11 lumbar spine BMD (D), chromosome 11 femoral neck BMD (E), and chromosome 22 lumbar spine BMD (F).

 
In the initial genome screen, a maximum LOD score of 1.97 with spine BMD was found on chromosome 11q at marker D11S987. Inclusion of all available Caucasian samples decreased the LOD score to 1.65 for spine BMD, whereas addition of the African-American samples increased the LOD score for spine to 1.75, with the peak LOD occurring near marker D11S1313. The LOD score for femoral neck BMD was 1.67 in the genome screen and decreased to 1.55 in the expanded Caucasian sample; both also occurred near D11S1313. Interestingly, the maximum LOD score for femoral neck BMD with the African-American samples included increased to 2.16 at the more centromeric marker D11S935. The initial genome screen LOD score of 2.13 on chromosome 22q for spine BMD decreased to 1.82 with the inclusion of additional Caucasian pairs and further declined to 0.99 in the combined Caucasian and African-American sample.


   Discussion
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
References
 
We conducted a genome scan for peak BMD in a sample of healthy Caucasian sister pairs and further pursued chromosomal regions with LOD scores above 1.85 at or near a marker locus in an expanded sample of Caucasian and African-American sister pairs. We report linkage of lumbar (L2–L4) spine BMD to chromosome 1q, with a maximum multipoint LOD score of 3.86 near D1S484. This LOD score surpasses the criteria (LOD >3.6) of Lander and Kruglyak (31) for genome-wide linkage significance. The region underlying our broad (26-cM) 1-LOD support interval for linkage on chromosome 1q includes several candidate genes with bone-related function, including the structural gene for osteocalcin, the interleukin-6 receptor, and a group of calcium-binding proteins. This chromosomal segment (1q21–23) includes the region linked to absorptive hypercalciuria with bone loss (32), but does not appear to overlap with the region reported by Devoto et al. (22) on chromosome 1p, who studied low BMD in seven extended pedigrees.

We also found suggestive evidence for linkage of femoral neck BMD to chromosome 5q, with a multipoint LOD score of 2.23 near D5S422. Potential candidate loci mapping to this region include the structural genes for osteonectin, believed to be responsible for the bone-specific calcification of collagen, and platelet-derived growth factor receptor-ß. Weaker evidence of linkage was found on chromosomes 6p, with a LOD score of 2.13 for lumbar spine BMD. The region of 6p implicated in spine BMD variation contains the gene for bone morphogenic protein-6, and may contain bone morphogenic protein-5 as well, although the latter locus is not well mapped relative to the microsatellite markers employed in our study. The evidence for linkage of spine BMD to chromosome 22q, observed in our initial genome scan, declined substantially (from a LOD score of 2.13 to 0.99) with genotyping of additional Caucasian and African-American sister pairs and probably represents a false positive linkage result.

The maximum LOD score on chromosome 11q in the Caucasian subset of our data for femoral neck BMD is 1.55, compared to 2.79 in our previous report (18). Since that report, 84 additional Caucasian sister pairs have been ascertained and genotyped for the current genome scan. This newly collected sample has greater evidence of linkage with the distal marker D11S937 and little evidence of linkage to D11S987 or D11S1313, the adjacent markers that provided the greatest linkage evidence in our initial report. Inclusion of the African-American sister pairs moves the linkage peak toward D11S935. This region of chromosome 11q (D11S935-D11S937) encompasses 34 cM. Inconsistent localization of the linkage finding in various subsets of our data within this broad region may indicate heterogeneity among our study group for genetic factors underlying BMD variability and/or the presence of 2 loci in this region of chromosome 11 affecting bone density. The identification of the genes for the 3 Mendelian bone-related phenotypes recently mapped to this region of 11q (19, 20, 21) will provide candidate genes that can be evaluated for their contribution to normal variation in bone density. In addition, linkage of BMD in other species to regions homologous to human chromosome 11q12–13 has been reported in a large sample of baboons (33), as well as by Klein et al. (24) in a study of peak total body BMD in mouse.

With the exception of the finding on chromosome 11q, none of the regions identified showed evidence of linkage with LOD scores above 1.0 to BMD at skeletal sites other than the one providing the primary linkage finding. Thus, in our sample we failed to detect loci (apart from the 11q locus) with substantial effect on BMD at multiple sites or across the entire skeleton. Each of the loci detected on chromosomes 1, 5, and 6 appears to affect primarily spine or hip BMD, not both of these skeletal sites.

Our collection of 595 sister pairs is the largest sample collected to date specifically to identify genes influencing BMD. This sample has power to detect chromosomal regions with evidence for linkage, as demonstrated by our finding on chromosome 1, where the maximum LOD score was 3.8. Our own simulation studies have produced a mean LOD score of 2.0 with Mapmaker/SIBS for a sample of similar size and structure to this one, for a gene accounting for 25% of the phenotypic variance and an overall trait heritability of 80%. All linkage results presented here are near or above this mean LOD score, thus demonstrating the power of our sample to detect QTLs of moderate to large effect.

We report linkage to several broad chromosomal regions and are pursuing saturation mapping with additional markers in these regions. We are in the process of collecting 600 additional sister pairs (400 Caucasian and 200 African-American). This greatly enlarged sample and increased marker density will enable us to confirm the linkage findings we reported here as well as to map the QTLs in these regions with greater accuracy for subsequent positional cloning and increase our power to detect additional loci of smaller effect contributing to bone density. Peak bone density is one of the best predictors of fracture risk, and elucidation of the genes contributing to normal variation in peak BMD will probably provide molecular targets for future therapeutic interventions designed to prevent osteoporosis and associated fractures.


   Acknowledgments
 
We gratefully acknowledge the sisters and parents who participated in this study, as well as the study coordinators, without whom this work could not have been accomplished.


   Footnotes
 
1 This work was supported by USPHS Grants RO1-AR-43476, MOI-00750, and Medical and Molecular Genetics Training Grant T32-HD-07373 and in part by a collaboration between Hoffman-La Roche/Roche Molecular Biochemicals and Axys Pharmaceuticals, Inc. Back

Received December 2, 1999.

Revised March 29, 2000.

Revised May 11, 2000.

Accepted May 19, 2000.


   References
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 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 

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[Abstract] [Full Text] [PDF]

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G. Carn, D. L. Koller, M. Peacock, S. L. Hui, W. E. Evans, P. M. Conneally, C. C. Johnston Jr., T. Foroud, and M. J. Econs
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[Abstract] [Full Text] [PDF]

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M. Peacock, C. H. Turner, M. J. Econs, and T. Foroud
Genetics of Osteoporosis
Endocr. Rev., June 1, 2002; 23(3): 303 - 326.
[Abstract] [Full Text] [PDF]

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S. H. Ralston
Genetic Control of Susceptibility to Osteoporosis
J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2460 - 2466.
[Abstract] [Full Text] [PDF]

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R. D. Hockett, S. C. Kirkwood, B. H. Mitlak, and W. H. Dere
Pharmacogenomics in Endocrinology
J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2495 - 2499.
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M. J. Econs and T. Foroud
The Genetics of Absorptive Hypercalciuria--A Note of Caution
J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1473 - 1475.
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B. Y. Reed, W. L. Gitomer, H. J. Heller, M. C. Hsu, M. Lemke, P. Padalino, and C. Y. C. Pak
Identification and Characterization of a Gene with Base Substitutions Associated with the Absorptive Hypercalciuria Phenotype and Low Spinal Bone Density
J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1476 - 1485.
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M. Devoto, C. Specchia, H.-H. Li, J. Caminis, A. Tenenhouse, H. Rodriguez, and L. D. Spotila
Variance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosome 1p36
Hum. Mol. Genet., October 1, 2001; 10(21): 2447 - 2452.
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H.-W. Deng, F.-H. Xu, T. Conway, X.-T. Deng, J.-L. Li, K. M. Davies, H. Deng, M. Johnson, and R. R. Recker
Is Population Bone Mineral Density Variation Linked to the Marker D11S987 On Chromosome 11q12-13?
J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3735 - 3741.
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C. I Amos and M. de Andrade
Genetic linkage methods for quantitative traits
Statistical Methods in Medical Research, February 1, 2001; 10(1): 3 - 25.
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