QTL with pleiotropic effects on serum levels of bone-specific alkaline phosphatase and osteocalcin maps to the baboon ortholog of human chromosome 6p23-21.3

Lorena M. Havill, Jeffrey Rogers, Laura A. Cox, Michael C. Mahaney

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Bone ALP and OC are under partial genetic control. This study of 591 pedigreed baboons shows a QTL corresponding to human 6p23-21.3 that accounts for 25% (bone ALP) and 20% (OC) of the genetic variance. A gene affecting osteoblast activity, number, or recruitment likely resides in this area. Introduction: Serum levels of bone alkaline phosphatase (ALP) and osteocalcin (OC) reflect osteoblast activity. Both of these measures are under partial genetic control. Genetic effects on bone ALP have not been previously localized to chromosomal regions in primates, nor has the degree to which genetic effects are shared (pleiotropic) between bone ALP and OC been studied. Materials and Methods: We applied variance components methods to a sample of 591 adult pedigreed baboons to detect and quantify effects of genes that influence bone ALP and that have pleiotropic effects on bone ALP and OC. A univariate linkage analysis was conducted for bone ALP. Bivariate linkage analyses were conducted in areas for which the bone ALP results presented here and a previous univariate OC linkage analysis showed evidence for linkage on the same chromosome for both bone ALP and OC. Results: A quantitative trait locus (QTL) for serum levels of bone ALP is evident on the baboon ortholog of human chromosomal region 6p (LOD 2.93). Thirty-seven percent (genetic correlation [ρG] = 0.61) of the genetic variance in bone ALP and OC is caused by pleiotropic effects of the same gene(s). Bivariate linkage analysis revealed a QTL in the region corresponding to human chromosome 6p23-21.3, with the strongest evidence for bivariate linkage near D6S422 (LOD = 2.97 at 22 cM from our pter-most marker). D6S422 maps to 20.4 Mb in the human genome. The QTL-specific heritability (h2) is 0.25 and 0.20 for bone ALP and OC, respectively. Conclusions: This first formal test for shared genetic effects on two serum markers of osteoblast activity indicates that a significant pleiotropic effect on bone ALP and OC levels, and thus on bone formation, is detectible. The fact that this region corresponds to one on mouse chromosome 13 that has repeatedly yielded QTLs for BMD should encourage more intensive study of the effect of genes in this region on bone maintenance and turnover.

Original languageEnglish (US)
Pages (from-to)1888-1896
Number of pages9
JournalJournal of Bone and Mineral Research
Volume21
Issue number12
DOIs
StatePublished - Dec 2006
Externally publishedYes

Fingerprint

Papio
Quantitative Trait Loci
Osteocalcin
Human Chromosomes
Alkaline Phosphatase
Bone and Bones
Serum
Osteoblasts
Genes
Chromosomes, Human, Pair 13
Bone Remodeling
Human Genome
Osteogenesis
Primates

Keywords

  • Animal models
  • Bone formation
  • Bone turnover
  • Skeletal genetics
  • Variance components

ASJC Scopus subject areas

  • Surgery

Cite this

QTL with pleiotropic effects on serum levels of bone-specific alkaline phosphatase and osteocalcin maps to the baboon ortholog of human chromosome 6p23-21.3. / Havill, Lorena M.; Rogers, Jeffrey; Cox, Laura A.; Mahaney, Michael C.

In: Journal of Bone and Mineral Research, Vol. 21, No. 12, 12.2006, p. 1888-1896.

Research output: Contribution to journalArticle

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title = "QTL with pleiotropic effects on serum levels of bone-specific alkaline phosphatase and osteocalcin maps to the baboon ortholog of human chromosome 6p23-21.3",
abstract = "Bone ALP and OC are under partial genetic control. This study of 591 pedigreed baboons shows a QTL corresponding to human 6p23-21.3 that accounts for 25{\%} (bone ALP) and 20{\%} (OC) of the genetic variance. A gene affecting osteoblast activity, number, or recruitment likely resides in this area. Introduction: Serum levels of bone alkaline phosphatase (ALP) and osteocalcin (OC) reflect osteoblast activity. Both of these measures are under partial genetic control. Genetic effects on bone ALP have not been previously localized to chromosomal regions in primates, nor has the degree to which genetic effects are shared (pleiotropic) between bone ALP and OC been studied. Materials and Methods: We applied variance components methods to a sample of 591 adult pedigreed baboons to detect and quantify effects of genes that influence bone ALP and that have pleiotropic effects on bone ALP and OC. A univariate linkage analysis was conducted for bone ALP. Bivariate linkage analyses were conducted in areas for which the bone ALP results presented here and a previous univariate OC linkage analysis showed evidence for linkage on the same chromosome for both bone ALP and OC. Results: A quantitative trait locus (QTL) for serum levels of bone ALP is evident on the baboon ortholog of human chromosomal region 6p (LOD 2.93). Thirty-seven percent (genetic correlation [ρG] = 0.61) of the genetic variance in bone ALP and OC is caused by pleiotropic effects of the same gene(s). Bivariate linkage analysis revealed a QTL in the region corresponding to human chromosome 6p23-21.3, with the strongest evidence for bivariate linkage near D6S422 (LOD = 2.97 at 22 cM from our pter-most marker). D6S422 maps to 20.4 Mb in the human genome. The QTL-specific heritability (h2) is 0.25 and 0.20 for bone ALP and OC, respectively. Conclusions: This first formal test for shared genetic effects on two serum markers of osteoblast activity indicates that a significant pleiotropic effect on bone ALP and OC levels, and thus on bone formation, is detectible. The fact that this region corresponds to one on mouse chromosome 13 that has repeatedly yielded QTLs for BMD should encourage more intensive study of the effect of genes in this region on bone maintenance and turnover.",
keywords = "Animal models, Bone formation, Bone turnover, Skeletal genetics, Variance components",
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T1 - QTL with pleiotropic effects on serum levels of bone-specific alkaline phosphatase and osteocalcin maps to the baboon ortholog of human chromosome 6p23-21.3

AU - Havill, Lorena M.

AU - Rogers, Jeffrey

AU - Cox, Laura A.

AU - Mahaney, Michael C.

PY - 2006/12

Y1 - 2006/12

N2 - Bone ALP and OC are under partial genetic control. This study of 591 pedigreed baboons shows a QTL corresponding to human 6p23-21.3 that accounts for 25% (bone ALP) and 20% (OC) of the genetic variance. A gene affecting osteoblast activity, number, or recruitment likely resides in this area. Introduction: Serum levels of bone alkaline phosphatase (ALP) and osteocalcin (OC) reflect osteoblast activity. Both of these measures are under partial genetic control. Genetic effects on bone ALP have not been previously localized to chromosomal regions in primates, nor has the degree to which genetic effects are shared (pleiotropic) between bone ALP and OC been studied. Materials and Methods: We applied variance components methods to a sample of 591 adult pedigreed baboons to detect and quantify effects of genes that influence bone ALP and that have pleiotropic effects on bone ALP and OC. A univariate linkage analysis was conducted for bone ALP. Bivariate linkage analyses were conducted in areas for which the bone ALP results presented here and a previous univariate OC linkage analysis showed evidence for linkage on the same chromosome for both bone ALP and OC. Results: A quantitative trait locus (QTL) for serum levels of bone ALP is evident on the baboon ortholog of human chromosomal region 6p (LOD 2.93). Thirty-seven percent (genetic correlation [ρG] = 0.61) of the genetic variance in bone ALP and OC is caused by pleiotropic effects of the same gene(s). Bivariate linkage analysis revealed a QTL in the region corresponding to human chromosome 6p23-21.3, with the strongest evidence for bivariate linkage near D6S422 (LOD = 2.97 at 22 cM from our pter-most marker). D6S422 maps to 20.4 Mb in the human genome. The QTL-specific heritability (h2) is 0.25 and 0.20 for bone ALP and OC, respectively. Conclusions: This first formal test for shared genetic effects on two serum markers of osteoblast activity indicates that a significant pleiotropic effect on bone ALP and OC levels, and thus on bone formation, is detectible. The fact that this region corresponds to one on mouse chromosome 13 that has repeatedly yielded QTLs for BMD should encourage more intensive study of the effect of genes in this region on bone maintenance and turnover.

AB - Bone ALP and OC are under partial genetic control. This study of 591 pedigreed baboons shows a QTL corresponding to human 6p23-21.3 that accounts for 25% (bone ALP) and 20% (OC) of the genetic variance. A gene affecting osteoblast activity, number, or recruitment likely resides in this area. Introduction: Serum levels of bone alkaline phosphatase (ALP) and osteocalcin (OC) reflect osteoblast activity. Both of these measures are under partial genetic control. Genetic effects on bone ALP have not been previously localized to chromosomal regions in primates, nor has the degree to which genetic effects are shared (pleiotropic) between bone ALP and OC been studied. Materials and Methods: We applied variance components methods to a sample of 591 adult pedigreed baboons to detect and quantify effects of genes that influence bone ALP and that have pleiotropic effects on bone ALP and OC. A univariate linkage analysis was conducted for bone ALP. Bivariate linkage analyses were conducted in areas for which the bone ALP results presented here and a previous univariate OC linkage analysis showed evidence for linkage on the same chromosome for both bone ALP and OC. Results: A quantitative trait locus (QTL) for serum levels of bone ALP is evident on the baboon ortholog of human chromosomal region 6p (LOD 2.93). Thirty-seven percent (genetic correlation [ρG] = 0.61) of the genetic variance in bone ALP and OC is caused by pleiotropic effects of the same gene(s). Bivariate linkage analysis revealed a QTL in the region corresponding to human chromosome 6p23-21.3, with the strongest evidence for bivariate linkage near D6S422 (LOD = 2.97 at 22 cM from our pter-most marker). D6S422 maps to 20.4 Mb in the human genome. The QTL-specific heritability (h2) is 0.25 and 0.20 for bone ALP and OC, respectively. Conclusions: This first formal test for shared genetic effects on two serum markers of osteoblast activity indicates that a significant pleiotropic effect on bone ALP and OC levels, and thus on bone formation, is detectible. The fact that this region corresponds to one on mouse chromosome 13 that has repeatedly yielded QTLs for BMD should encourage more intensive study of the effect of genes in this region on bone maintenance and turnover.

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KW - Bone formation

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