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Comparative Study
. 2003 Jan;72(1):144-55.
doi: 10.1086/345819. Epub 2002 Dec 11.

Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36

S G Wilson  1 , P W Reed, A Bansal, M Chiano, M Lindersson, M Langdown, R L Prince, D Thompson, E Thompson, M Bailey, P W Kleyn, P Sambrook, M M Shi, T D Spector
Affiliations
Comparative Study

Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36

S G Wilson et al. Am J Hum Genet. 2003 Jan.

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.

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Figures

Figure 1
Figure 1
Genomewide scans for QTL that regulate BMD in 1,094 twin pairs. A, lumbar spine. B, total hip. C, whole body. Equivalent LOD scores were calculated from the NPL Z scores output by MAPMAKER/SIBS, using the relationship Z2/4.6052 = 1 LOD.
Figure 2
Figure 2
Genomewide scans for QTL that regulate BMD in 254 pedigrees containing an EDAC pair. A, lumbar spine. B, total hip.
Figure 3
Figure 3
Comparison of linkage data for lumbar spine (o), total-hip (+) and whole-body (×) BMD in 1,094 unselected twin pairs and for lumbar spine (*) and total-hip (□) BMD in 254 pedigrees containing an EDAC pair at 1p36 (D1S468 to D1S199) (A), 3p22-14 (D3S1277 to D3S1566) (B), 11pter-14 (D11S4046 to D11S904) (C), 16p12-q23 (D16S3068 to D16S515) (D), and 19q13 (D19S414 to D19S571) (E).
See this image and copyright information in PMC

References

Electronic-Database Information

    1. Center for Medical Genetics, Marshfield Medical Research Foundation http://research.marshfieldclinic.org/genetics/ (for marker order and genetic distance between markers)
    1. Généthon, http://www.cephb.fr/bio/ceph-genethon-map.html (for marker order and genetic distance between markers)
    1. National Center for Biotechnology Information, http://www.ncbi.nlm.nih.gov/ (for identification of candidate genes in loci of interest)
    1. UCSC Genome Bioinformatics, http://genome.cse.ucsc.edu/ (for marker order and genetic distance between markers)

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