Comparison of Genome Screens for Two Independent Cohorts Provides Replication of Suggestive Linkage of Bone Mineral Density to 3p21 and 1p36

S.G. Wilson, P.W. Reed, A. Bansal, M. Chiano, M. Lindersson, M. Langdown, Richard Prince, D. Thompson, E. Thompson, M. Bailey, P.W. Kleyn, P. Sambrook, M.M. Shi, T.D. Spector

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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.
Original languageEnglish
Pages (from-to)144-155
JournalAmerican Journal of Human Genetics
Volume72
DOIs
Publication statusPublished - 2003

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Bone Density
Genome
Pedigree
Spine
Pelvic Bones
Chromosomes, Human, Pair 17
Osteoporotic Fractures
Quantitative Trait Loci
Genetic Association Studies
Organism Cloning
Cohort Studies
Chromosomes

Cite this

Wilson, S.G. ; Reed, P.W. ; Bansal, A. ; Chiano, M. ; Lindersson, M. ; Langdown, M. ; Prince, Richard ; Thompson, D. ; Thompson, E. ; Bailey, M. ; Kleyn, P.W. ; Sambrook, P. ; Shi, M.M. ; Spector, T.D. / Comparison of Genome Screens for Two Independent Cohorts Provides Replication of Suggestive Linkage of Bone Mineral Density to 3p21 and 1p36. In: American Journal of Human Genetics. 2003 ; Vol. 72. pp. 144-155.
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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.",
author = "S.G. Wilson and P.W. Reed and A. Bansal and M. Chiano and M. Lindersson and M. Langdown and Richard Prince and D. Thompson and E. Thompson and M. Bailey and P.W. Kleyn and P. Sambrook and M.M. Shi and T.D. Spector",
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Wilson, SG, Reed, PW, Bansal, A, Chiano, M, Lindersson, M, Langdown, M, Prince, R, Thompson, D, Thompson, E, Bailey, M, Kleyn, PW, Sambrook, P, Shi, MM & Spector, TD 2003, 'Comparison of Genome Screens for Two Independent Cohorts Provides Replication of Suggestive Linkage of Bone Mineral Density to 3p21 and 1p36' American Journal of Human Genetics, vol. 72, pp. 144-155. https://doi.org/10.1086/345819

Comparison of Genome Screens for Two Independent Cohorts Provides Replication of Suggestive Linkage of Bone Mineral Density to 3p21 and 1p36. / Wilson, S.G.; Reed, P.W.; Bansal, A.; Chiano, M.; Lindersson, M.; Langdown, M.; Prince, Richard; Thompson, D.; Thompson, E.; Bailey, M.; Kleyn, P.W.; Sambrook, P.; Shi, M.M.; Spector, T.D.

In: American Journal of Human Genetics, Vol. 72, 2003, p. 144-155.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Comparison of Genome Screens for Two Independent Cohorts Provides Replication of Suggestive Linkage of Bone Mineral Density to 3p21 and 1p36

AU - Wilson, S.G.

AU - Reed, P.W.

AU - Bansal, A.

AU - Chiano, M.

AU - Lindersson, M.

AU - Langdown, M.

AU - Prince, Richard

AU - Thompson, D.

AU - Thompson, E.

AU - Bailey, M.

AU - Kleyn, P.W.

AU - Sambrook, P.

AU - Shi, M.M.

AU - Spector, T.D.

PY - 2003

Y1 - 2003

N2 - 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.

AB - 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.

U2 - 10.1086/345819

DO - 10.1086/345819

M3 - Article

VL - 72

SP - 144

EP - 155

JO - The American Journal of Human Genetics

JF - The American Journal of Human Genetics

SN - 0002-9297

ER -