Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish

E. A. Streeten; T. J. Beck; J. R. O'Connell; Evadnie Rampersand; D. J. McBride; S. L. Takala; T. I. Pollin; K. Uusi-Rasi; B. D. Mitchell; A. R. Shuldiner

doi:10.1016/j.bone.2008.04.005

Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish

E. A. Streeten, T. J. Beck, J. R. O'Connell, Evadnie Rampersand, D. J. McBride, S. L. Takala, T. I. Pollin, K. Uusi-Rasi, B. D. Mitchell, A. R. Shuldiner

School of Medicine

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Introduction: Fracture risk is associated with bone mineral density (BMD) and with other indices of bone strength, including hip geometry. While the heritability and associated fracture risk of BMD are well described, less is known about genetic influences of bone geometry. We derived hip structural phenotypes using the Hip Structural Analysis program (HSA) and performed autosome-wide linkage analysis of hip geometric structural phenotypes. Materials and methods: The Amish Family Osteoporosis Study was designed to identify genes affecting bone health. BMD was measured at the hip using dual X-ray absorptiometry (DXA) in 879 participants (mean age ± SD = 49.8 ± 16.1 years, range 18-91 years) from large multigenerational families. From DXA scans, we computed structural measures of hip geometry at the femoral neck (NN) and shaft (S) by HSA, including cross-sectional area (CSA), endocortical or inner diameter (ID), outer diameter (OD) buckling ratio (BR) and section modulus (Z). Genotyping of 731 highly polymorphic microsatellite markers (average spacing of 5.4 cM) and autosome-wide multipoint linkage analysis was performed. Results: The heritability of HSA-derived hip phenotypes ranged from 40 to 84%. In the group as a whole, autosome-wide linkage analysis suggested evidence of linkage for QTLs related to NN_Z on chromosome 1p36 (LOD = 2.36). In subgroup analysis, ten additional suggestive regions of linkage were found on chromosomes 1, 2, 5, 6, 11, 12, 14, 15 and 17, all with LOD > 2.3 except for our linkage at 17q11.2-13 for men and women age 50 and under for NN_CSA, which had a lower LOD of 2.16, but confirmed a previous linkage report. Conclusions: We found HSA-derived measures of hip structure to be highly heritable independent of BMD. No strong evidence of linkage was found for any phenotype. Confirmatory evidence of linkage was found on chromosome 17q11.2-12 for NN_CSA. Modest evidence was found for genes affecting hip structural phenotypes at ten other chromosomal locations.

Original language	English (US)
Pages (from-to)	607-612
Number of pages	6
Journal	Bone
Volume	43
Issue number	3
DOIs	https://doi.org/10.1016/j.bone.2008.04.005
State	Published - Sep 2008

Keywords

Autosome-wide scan
Bone geometry
Genetics
Heritability
Hip structural phenotype

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Physiology
Histology

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10.1016/j.bone.2008.04.005

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@article{3be88800406241df81ddd168e1337cf0,

title = "Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish",

abstract = "Introduction: Fracture risk is associated with bone mineral density (BMD) and with other indices of bone strength, including hip geometry. While the heritability and associated fracture risk of BMD are well described, less is known about genetic influences of bone geometry. We derived hip structural phenotypes using the Hip Structural Analysis program (HSA) and performed autosome-wide linkage analysis of hip geometric structural phenotypes. Materials and methods: The Amish Family Osteoporosis Study was designed to identify genes affecting bone health. BMD was measured at the hip using dual X-ray absorptiometry (DXA) in 879 participants (mean age ± SD = 49.8 ± 16.1 years, range 18-91 years) from large multigenerational families. From DXA scans, we computed structural measures of hip geometry at the femoral neck (NN) and shaft (S) by HSA, including cross-sectional area (CSA), endocortical or inner diameter (ID), outer diameter (OD) buckling ratio (BR) and section modulus (Z). Genotyping of 731 highly polymorphic microsatellite markers (average spacing of 5.4 cM) and autosome-wide multipoint linkage analysis was performed. Results: The heritability of HSA-derived hip phenotypes ranged from 40 to 84%. In the group as a whole, autosome-wide linkage analysis suggested evidence of linkage for QTLs related to NN_Z on chromosome 1p36 (LOD = 2.36). In subgroup analysis, ten additional suggestive regions of linkage were found on chromosomes 1, 2, 5, 6, 11, 12, 14, 15 and 17, all with LOD > 2.3 except for our linkage at 17q11.2-13 for men and women age 50 and under for NN_CSA, which had a lower LOD of 2.16, but confirmed a previous linkage report. Conclusions: We found HSA-derived measures of hip structure to be highly heritable independent of BMD. No strong evidence of linkage was found for any phenotype. Confirmatory evidence of linkage was found on chromosome 17q11.2-12 for NN_CSA. Modest evidence was found for genes affecting hip structural phenotypes at ten other chromosomal locations.",

keywords = "Autosome-wide scan, Bone geometry, Genetics, Heritability, Hip structural phenotype",

author = "Streeten, {E. A.} and Beck, {T. J.} and O'Connell, {J. R.} and Evadnie Rampersand and McBride, {D. J.} and Takala, {S. L.} and Pollin, {T. I.} and K. Uusi-Rasi and Mitchell, {B. D.} and Shuldiner, {A. R.}",

note = "Funding Information: This work was supported by research grants RO1-AR46838, RO1-AG18728, and RO1-HL69313 awarded by the National Institutes of Health, the University of Maryland General Clinical Research Center, Grant M01 RR 16500 and Hopkins Bayview General Clinical Research Center, Grant M01 RR02719, General Clinical Research Centers Program, National Center for Research Resources (NCRR), NIH, the NHLBI Mammalian Genotyping Service, Marshfield Medical Research Foundation, Marshfield, WI, and the Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC). ",

year = "2008",

month = sep,

doi = "10.1016/j.bone.2008.04.005",

language = "English (US)",

volume = "43",

pages = "607--612",

journal = "Bone",

issn = "8756-3282",

publisher = "Elsevier Inc.",

number = "3",

}

TY - JOUR

T1 - Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish

AU - Streeten, E. A.

AU - Beck, T. J.

AU - O'Connell, J. R.

AU - Rampersand, Evadnie

AU - McBride, D. J.

AU - Takala, S. L.

AU - Pollin, T. I.

AU - Uusi-Rasi, K.

AU - Mitchell, B. D.

AU - Shuldiner, A. R.

N1 - Funding Information: This work was supported by research grants RO1-AR46838, RO1-AG18728, and RO1-HL69313 awarded by the National Institutes of Health, the University of Maryland General Clinical Research Center, Grant M01 RR 16500 and Hopkins Bayview General Clinical Research Center, Grant M01 RR02719, General Clinical Research Centers Program, National Center for Research Resources (NCRR), NIH, the NHLBI Mammalian Genotyping Service, Marshfield Medical Research Foundation, Marshfield, WI, and the Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC).

PY - 2008/9

Y1 - 2008/9

N2 - Introduction: Fracture risk is associated with bone mineral density (BMD) and with other indices of bone strength, including hip geometry. While the heritability and associated fracture risk of BMD are well described, less is known about genetic influences of bone geometry. We derived hip structural phenotypes using the Hip Structural Analysis program (HSA) and performed autosome-wide linkage analysis of hip geometric structural phenotypes. Materials and methods: The Amish Family Osteoporosis Study was designed to identify genes affecting bone health. BMD was measured at the hip using dual X-ray absorptiometry (DXA) in 879 participants (mean age ± SD = 49.8 ± 16.1 years, range 18-91 years) from large multigenerational families. From DXA scans, we computed structural measures of hip geometry at the femoral neck (NN) and shaft (S) by HSA, including cross-sectional area (CSA), endocortical or inner diameter (ID), outer diameter (OD) buckling ratio (BR) and section modulus (Z). Genotyping of 731 highly polymorphic microsatellite markers (average spacing of 5.4 cM) and autosome-wide multipoint linkage analysis was performed. Results: The heritability of HSA-derived hip phenotypes ranged from 40 to 84%. In the group as a whole, autosome-wide linkage analysis suggested evidence of linkage for QTLs related to NN_Z on chromosome 1p36 (LOD = 2.36). In subgroup analysis, ten additional suggestive regions of linkage were found on chromosomes 1, 2, 5, 6, 11, 12, 14, 15 and 17, all with LOD > 2.3 except for our linkage at 17q11.2-13 for men and women age 50 and under for NN_CSA, which had a lower LOD of 2.16, but confirmed a previous linkage report. Conclusions: We found HSA-derived measures of hip structure to be highly heritable independent of BMD. No strong evidence of linkage was found for any phenotype. Confirmatory evidence of linkage was found on chromosome 17q11.2-12 for NN_CSA. Modest evidence was found for genes affecting hip structural phenotypes at ten other chromosomal locations.

AB - Introduction: Fracture risk is associated with bone mineral density (BMD) and with other indices of bone strength, including hip geometry. While the heritability and associated fracture risk of BMD are well described, less is known about genetic influences of bone geometry. We derived hip structural phenotypes using the Hip Structural Analysis program (HSA) and performed autosome-wide linkage analysis of hip geometric structural phenotypes. Materials and methods: The Amish Family Osteoporosis Study was designed to identify genes affecting bone health. BMD was measured at the hip using dual X-ray absorptiometry (DXA) in 879 participants (mean age ± SD = 49.8 ± 16.1 years, range 18-91 years) from large multigenerational families. From DXA scans, we computed structural measures of hip geometry at the femoral neck (NN) and shaft (S) by HSA, including cross-sectional area (CSA), endocortical or inner diameter (ID), outer diameter (OD) buckling ratio (BR) and section modulus (Z). Genotyping of 731 highly polymorphic microsatellite markers (average spacing of 5.4 cM) and autosome-wide multipoint linkage analysis was performed. Results: The heritability of HSA-derived hip phenotypes ranged from 40 to 84%. In the group as a whole, autosome-wide linkage analysis suggested evidence of linkage for QTLs related to NN_Z on chromosome 1p36 (LOD = 2.36). In subgroup analysis, ten additional suggestive regions of linkage were found on chromosomes 1, 2, 5, 6, 11, 12, 14, 15 and 17, all with LOD > 2.3 except for our linkage at 17q11.2-13 for men and women age 50 and under for NN_CSA, which had a lower LOD of 2.16, but confirmed a previous linkage report. Conclusions: We found HSA-derived measures of hip structure to be highly heritable independent of BMD. No strong evidence of linkage was found for any phenotype. Confirmatory evidence of linkage was found on chromosome 17q11.2-12 for NN_CSA. Modest evidence was found for genes affecting hip structural phenotypes at ten other chromosomal locations.

KW - Autosome-wide scan

KW - Bone geometry

KW - Genetics

KW - Heritability

KW - Hip structural phenotype

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UR - http://www.scopus.com/inward/citedby.url?scp=49149119223&partnerID=8YFLogxK

U2 - 10.1016/j.bone.2008.04.005

DO - 10.1016/j.bone.2008.04.005

M3 - Article

C2 - 18555766

AN - SCOPUS:49149119223

SN - 8756-3282

VL - 43

SP - 607

EP - 612

JO - Bone

JF - Bone

IS - 3

ER -

Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish

Abstract

Keywords

ASJC Scopus subject areas

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