High-resolution genome screen for bone mineral density in heterogeneous stock rat

Imranul Alam, Daniel L. Koller, Toni Cañete, Gloria Blázquez, Regina López-Aumatell, Esther Martínez-Membrives, Sira Díaz-Morán, Adolf Tobeña, Alberto Fernández-Teruel, Pernilla Stridh, Margarita Diez, Tomas Olsson, Martina Johannesson, Amelie Baud, Michael Econs, Tatiana Foroud

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

We previously demonstrated that skeletal mass, structure, and biomechanical properties vary considerably in heterogeneous stock (HS) rat strains. In addition, we observed strong heritability for several of these skeletal phenotypes in the HS rat model, suggesting that it represents a unique genetic resource for dissecting the complex genetics underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone mineral density in HS rats. We measured bone phenotypes from 1524 adult male and female HS rats between 17 and 20 weeks of age. Phenotypes included dual-energy X-ray absorptiometry (DXA) measurements for bone mineral content and areal bone mineral density (aBMD) for femur and lumbar spine (L3-L5), and volumetric BMD measurements by CT for the midshaft and distal femur, femur neck, and fifth lumbar vertebra (L5). A total of 70,000 polymorphic single-nucleotide polymorphisms (SNPs) distributed throughout the genome were selected from genotypes obtained from the Affymetrix rat custom SNPs array for the HS rat population. These SNPs spanned the HS rat genome with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent for each genotyped locus from each of the eight founder HS strains. The haplotypes were tested for association with each bone density phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for BMD phenotypes on chromosomes 2, 9, 10, and 13 meeting a conservative genomewide empiric significance threshold (false discovery rate [FDR] = 5%; p < 3 × 10-6). Importantly, most QTLs were localized to very small genomic regions (1-3 megabases [Mb]), allowing us to identify a narrow set of potential candidate genes including both novel genes and genes previously shown to have roles in skeletal development and homeostasis.

Original languageEnglish
Pages (from-to)1619-1626
Number of pages8
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume29
Issue number7
DOIs
StatePublished - 2014

Fingerprint

Bone Density
Genome
Single Nucleotide Polymorphism
Phenotype
Haplotypes
Quantitative Trait Loci
Femur
Genes
Bone and Bones
Lumbar Vertebrae
Chromosomes, Human, Pair 9
Chromosomes, Human, Pair 2
Femur Neck
Linkage Disequilibrium
Photon Absorptiometry
Spine
Homeostasis
Genotype
Population

Keywords

  • BONE DENSITY
  • GENES
  • GENETICS
  • HETEROGENEOUS STOCK RAT
  • OSTEOPOROSIS

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

High-resolution genome screen for bone mineral density in heterogeneous stock rat. / Alam, Imranul; Koller, Daniel L.; Cañete, Toni; Blázquez, Gloria; López-Aumatell, Regina; Martínez-Membrives, Esther; Díaz-Morán, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Stridh, Pernilla; Diez, Margarita; Olsson, Tomas; Johannesson, Martina; Baud, Amelie; Econs, Michael; Foroud, Tatiana.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 29, No. 7, 2014, p. 1619-1626.

Research output: Contribution to journalArticle

Alam, I, Koller, DL, Cañete, T, Blázquez, G, López-Aumatell, R, Martínez-Membrives, E, Díaz-Morán, S, Tobeña, A, Fernández-Teruel, A, Stridh, P, Diez, M, Olsson, T, Johannesson, M, Baud, A, Econs, M & Foroud, T 2014, 'High-resolution genome screen for bone mineral density in heterogeneous stock rat', Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, vol. 29, no. 7, pp. 1619-1626. https://doi.org/10.1002/jbmr.2195
Alam, Imranul ; Koller, Daniel L. ; Cañete, Toni ; Blázquez, Gloria ; López-Aumatell, Regina ; Martínez-Membrives, Esther ; Díaz-Morán, Sira ; Tobeña, Adolf ; Fernández-Teruel, Alberto ; Stridh, Pernilla ; Diez, Margarita ; Olsson, Tomas ; Johannesson, Martina ; Baud, Amelie ; Econs, Michael ; Foroud, Tatiana. / High-resolution genome screen for bone mineral density in heterogeneous stock rat. In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014 ; Vol. 29, No. 7. pp. 1619-1626.
@article{73c4a52a1dda4bf8bfbd2224e23faf60,
title = "High-resolution genome screen for bone mineral density in heterogeneous stock rat",
abstract = "We previously demonstrated that skeletal mass, structure, and biomechanical properties vary considerably in heterogeneous stock (HS) rat strains. In addition, we observed strong heritability for several of these skeletal phenotypes in the HS rat model, suggesting that it represents a unique genetic resource for dissecting the complex genetics underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone mineral density in HS rats. We measured bone phenotypes from 1524 adult male and female HS rats between 17 and 20 weeks of age. Phenotypes included dual-energy X-ray absorptiometry (DXA) measurements for bone mineral content and areal bone mineral density (aBMD) for femur and lumbar spine (L3-L5), and volumetric BMD measurements by CT for the midshaft and distal femur, femur neck, and fifth lumbar vertebra (L5). A total of 70,000 polymorphic single-nucleotide polymorphisms (SNPs) distributed throughout the genome were selected from genotypes obtained from the Affymetrix rat custom SNPs array for the HS rat population. These SNPs spanned the HS rat genome with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent for each genotyped locus from each of the eight founder HS strains. The haplotypes were tested for association with each bone density phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for BMD phenotypes on chromosomes 2, 9, 10, and 13 meeting a conservative genomewide empiric significance threshold (false discovery rate [FDR] = 5{\%}; p < 3 × 10-6). Importantly, most QTLs were localized to very small genomic regions (1-3 megabases [Mb]), allowing us to identify a narrow set of potential candidate genes including both novel genes and genes previously shown to have roles in skeletal development and homeostasis.",
keywords = "BONE DENSITY, GENES, GENETICS, HETEROGENEOUS STOCK RAT, OSTEOPOROSIS",
author = "Imranul Alam and Koller, {Daniel L.} and Toni Ca{\~n}ete and Gloria Bl{\'a}zquez and Regina L{\'o}pez-Aumatell and Esther Mart{\'i}nez-Membrives and Sira D{\'i}az-Mor{\'a}n and Adolf Tobe{\~n}a and Alberto Fern{\'a}ndez-Teruel and Pernilla Stridh and Margarita Diez and Tomas Olsson and Martina Johannesson and Amelie Baud and Michael Econs and Tatiana Foroud",
year = "2014",
doi = "10.1002/jbmr.2195",
language = "English",
volume = "29",
pages = "1619--1626",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "7",

}

TY - JOUR

T1 - High-resolution genome screen for bone mineral density in heterogeneous stock rat

AU - Alam, Imranul

AU - Koller, Daniel L.

AU - Cañete, Toni

AU - Blázquez, Gloria

AU - López-Aumatell, Regina

AU - Martínez-Membrives, Esther

AU - Díaz-Morán, Sira

AU - Tobeña, Adolf

AU - Fernández-Teruel, Alberto

AU - Stridh, Pernilla

AU - Diez, Margarita

AU - Olsson, Tomas

AU - Johannesson, Martina

AU - Baud, Amelie

AU - Econs, Michael

AU - Foroud, Tatiana

PY - 2014

Y1 - 2014

N2 - We previously demonstrated that skeletal mass, structure, and biomechanical properties vary considerably in heterogeneous stock (HS) rat strains. In addition, we observed strong heritability for several of these skeletal phenotypes in the HS rat model, suggesting that it represents a unique genetic resource for dissecting the complex genetics underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone mineral density in HS rats. We measured bone phenotypes from 1524 adult male and female HS rats between 17 and 20 weeks of age. Phenotypes included dual-energy X-ray absorptiometry (DXA) measurements for bone mineral content and areal bone mineral density (aBMD) for femur and lumbar spine (L3-L5), and volumetric BMD measurements by CT for the midshaft and distal femur, femur neck, and fifth lumbar vertebra (L5). A total of 70,000 polymorphic single-nucleotide polymorphisms (SNPs) distributed throughout the genome were selected from genotypes obtained from the Affymetrix rat custom SNPs array for the HS rat population. These SNPs spanned the HS rat genome with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent for each genotyped locus from each of the eight founder HS strains. The haplotypes were tested for association with each bone density phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for BMD phenotypes on chromosomes 2, 9, 10, and 13 meeting a conservative genomewide empiric significance threshold (false discovery rate [FDR] = 5%; p < 3 × 10-6). Importantly, most QTLs were localized to very small genomic regions (1-3 megabases [Mb]), allowing us to identify a narrow set of potential candidate genes including both novel genes and genes previously shown to have roles in skeletal development and homeostasis.

AB - We previously demonstrated that skeletal mass, structure, and biomechanical properties vary considerably in heterogeneous stock (HS) rat strains. In addition, we observed strong heritability for several of these skeletal phenotypes in the HS rat model, suggesting that it represents a unique genetic resource for dissecting the complex genetics underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone mineral density in HS rats. We measured bone phenotypes from 1524 adult male and female HS rats between 17 and 20 weeks of age. Phenotypes included dual-energy X-ray absorptiometry (DXA) measurements for bone mineral content and areal bone mineral density (aBMD) for femur and lumbar spine (L3-L5), and volumetric BMD measurements by CT for the midshaft and distal femur, femur neck, and fifth lumbar vertebra (L5). A total of 70,000 polymorphic single-nucleotide polymorphisms (SNPs) distributed throughout the genome were selected from genotypes obtained from the Affymetrix rat custom SNPs array for the HS rat population. These SNPs spanned the HS rat genome with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent for each genotyped locus from each of the eight founder HS strains. The haplotypes were tested for association with each bone density phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for BMD phenotypes on chromosomes 2, 9, 10, and 13 meeting a conservative genomewide empiric significance threshold (false discovery rate [FDR] = 5%; p < 3 × 10-6). Importantly, most QTLs were localized to very small genomic regions (1-3 megabases [Mb]), allowing us to identify a narrow set of potential candidate genes including both novel genes and genes previously shown to have roles in skeletal development and homeostasis.

KW - BONE DENSITY

KW - GENES

KW - GENETICS

KW - HETEROGENEOUS STOCK RAT

KW - OSTEOPOROSIS

UR - http://www.scopus.com/inward/record.url?scp=84903288901&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903288901&partnerID=8YFLogxK

U2 - 10.1002/jbmr.2195

DO - 10.1002/jbmr.2195

M3 - Article

C2 - 24643965

AN - SCOPUS:84903288901

VL - 29

SP - 1619

EP - 1626

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 7

ER -