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High resolution linkage and linkage disequilibrium analyses of chromosome 1p36 SNPs identify new positional candidate genes for low bone mineral density

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Abstract

Summary

A quantitative trait locus (QTL) for BMD maps to chromosome 1p36. We have analyzed a high density SNP panel from this region for linkage and association to BMD in 39 osteoporosis pedigrees. Our results support the presence of genes controlling BMD on 1p36 and indicate new candidates for further analyses.

Introduction

Low BMD is one of the major risk factors for osteoporosis. Following a genome scan in a sample of Caucasian families recruited through probands with low BMD, a region on 1p36 near marker D1S214 received support as a QTL for BMD from linkage (maximum lod-score = 2.87) and linkage disequilibrium (LD) analysis (p < 0.01).

Methods

To better characterize the genetic risk factors for low BMD located in this genomic region, we have genotyped the same group of families for 1095 SNPs located across 11 Mb on 1p36. Linkage and LD analyses have been performed using the variance component approach.

Results

Multivariate linkage analysis indicated two QTLs for femoral neck BMD, lumbar spine BMD and trochanter BMD simultaneously on 1p36, with maximum lod-scores of 4.37 at 12 cM and 3.59 at 22 cM. LD analysis identified several SNPs potentially associated with BMD, including the RERE gene SNP rs11121179 (p  = 0.000005 for lumbar spine BMD). Other candidate genes include G1P2, SSU72 and CCDC27 (each containing 1 SNP with p < 0.001 for at least one BMD trait).

Conclusions

This study supports the presence in 1p36 of QTLs affecting BMD at multiple skeletal sites. Replication of our results in other independent cohorts is warranted.

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Acknowledgments

The authors acknowledge the assistance of Dr. Alan Tenenhouse with the pedigree collection. The authors would also like to thank the co-authors of reference 10 for granting permission to cite unpublished results from the collaborative meta-analysis. This work was supported in part by a research grant from the National Osteoporosis Foundation.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Division of Human Genetics, The Children’s Hospital of Philadelphia, Room 1002 ARC Bldg, 3615 Civic Center Blvd, Philadelphia, PA, 19104-4399, USA

    H. Zhang, H. Rydbeck & M. Devoto

  2. Nemours Children’s Clinic, Wilmington, DE, USA

    K. Sol-Church & D. Stabley

  3. ScienceScribe, Haddonfield, NJ, USA

    L. D. Spotila

  4. Department of Pediatrics and Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    M. Devoto

  5. Department of Experimental Medicine, University La Sapienza, Rome, Italy

    M. Devoto

Authors
  1. H. Zhang
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  2. K. Sol-Church
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  3. H. Rydbeck
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  4. D. Stabley
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  5. L. D. Spotila
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  6. M. Devoto
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Corresponding author

Correspondence to M. Devoto.

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Table 1S

Results of QTLD analysis for selected SNPs (p < 0.01) corresponding to Figure 1 (DOC 133 KB)

Table 2S

Results of QTLD analysis for all SNPs in the RERE gene region (DOC 83.5 KB)

High resolution image file (TIF 59.6 KB)

Fig. 1S

Pattern of LD in a region of 11 Mb (NCBI Build 35) on 1p36. The lines indicate mean pair-wise D’ (A) and r 2 (B) in a 500-kb sliding window (solid line: HapMap CEU population, dot line: our sample) (GIF 94.6 KB)

Fig. 2S

High resolution image file (TIF 233 KB)

Fig. 2S

LD test results in part of the RERE gene (DNA size 465.07 kb, mRNA size 8026 bp, 24 exons) and the genomic regions on the 3’ side of the gene on chromosome 1p36 between 8,325,000 and 8,475,000 base pairs (NCBI Build 35). (A) Negative log10 association P-values for FN, LS and TR BMD, respectively. (B) Pairwise r 2 plot from International HapMap CEU population data in the same region, where the intensity of the shading corresponds to different values of the disequilibrium coefficient r 2. The most significant marker, rs11121179, is contained within a large block of LD. Another less significant marker (rs301810, 0.001 < P < 0.01) is located within a smaller adjacent block (GIF 245 KB)

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Zhang, H., Sol-Church, K., Rydbeck, H. et al. High resolution linkage and linkage disequilibrium analyses of chromosome 1p36 SNPs identify new positional candidate genes for low bone mineral density. Osteoporos Int 20, 341–346 (2009). https://doi.org/10.1007/s00198-008-0668-1

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  • DOI: https://doi.org/10.1007/s00198-008-0668-1

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