A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations

Michelle S. Yau; Allison L. Kuipers; Ryan Price; Aude Nicolas; Salman M. Tajuddin; Samuel K. Handelman; Liubov Arbeeva; Alessandra Chesi; Yi Hsiang Hsu; Ching Ti Liu; David Karasik; Babette S. Zemel; Struan F.A. Grant; Joanne M. Jordan; Rebecca D. Jackson; Michele K. Evans; Tamara B. Harris; Joseph M. Zmuda; Douglas P. Kiel

doi:10.1002/jbmr.4220

A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations

Michelle S. Yau, Allison L. Kuipers, Ryan Price, Aude Nicolas, Salman M. Tajuddin, Samuel K. Handelman, Liubov Arbeeva, Alessandra Chesi, Yi Hsiang Hsu, Ching Ti Liu, David Karasik, Babette S. Zemel, Struan F.A. Grant, Joanne M. Jordan, Rebecca D. Jackson, Michele K. Evans, Tamara B. Harris, Joseph M. Zmuda, Douglas P. Kiel

Bar-Ilan University - Azrieli Faculty of Medicine

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

8 Scopus citations

Abstract

Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I² index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10⁻⁴), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10⁻⁴) and 7q31 (WNT16, p = 2.96 × 10⁻⁵), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p < 2.23 × 10⁻⁴), 11q14 (DCDC5, p < 5.35 × 10⁻⁵), and 17p13 (SMG6, p < 6.78 × 10⁻⁵) that were not tagged by European ancestry index SNPs. Rare single-nucleotide variants in AKAP11 (p = 2.32 × 10⁻²), MBL2 (p = 4.09 × 10⁻²), MEPE (p = 3.15 × 10⁻²), SLC25A13 (p = 3.03 × 10⁻²), STARD3NL (p = 3.35 × 10⁻²), and TNFRSF11A (p = 3.18 × 10⁻³) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power and to identify both other loci that are transferable across populations and novel population-specific variants.

Original language	English
Pages (from-to)	469-479
Number of pages	11
Journal	Journal of Bone and Mineral Research
Volume	36
Issue number	3
DOIs	https://doi.org/10.1002/jbmr.4220
State	Published - Mar 2021

Bibliographical note

Publisher Copyright:
© 2020 American Society for Bone and Mineral Research (ASBMR)

Funding

Funding sources include NIAMS R01-AR041398, 5-P60-AR30701, R01-AR049747, R01-AR051124, 5-P60-AR49465, and 5-P60-AR062760; NIA T32-AG023480 and R01-AG033618; CDC/ASPPH S043, S1734, and S3486; CDC U01DP003206 and U01DP006266; and Algynomics, Inc. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This manuscript was prepared in collaboration with investigators of the WHI and has been reviewed and approved by the Women's Health Initiative (WHI). WHI investigators are listed at http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf. Authors' roles: Study design: MSY, YH, CTL, DK, and DPK. Study conduct: All. Data collection: BSZ, SFAG, JMJ, RDJ, MKE, TBH, JMZ, and DPK. Data analysis: MSY, ALK, RP, AN, SMT, SKH, LA, and AC. Data interpretation: All. Drafting manuscript: MSY. Revising manuscript content: All. Approving final version of manuscript: All. MSY takes responsibility for the integrity of the data analysis. Author Contributions: MSY: Formal analysis; investigation; methodology; writing-original draft; writing-review and editing. ALK: Formal analysis; investigation; writing-review and editing. RP: Formal analysis; investigation; writing-review and editing. AN: Formal analysis; investigation; writing-review and editing. SMT: Formal analysis; investigation; writing-review and editing. SKH: Formal analysis; investigation; writing-review and editing. LA: Formal analysis; investigation; writing-review and editing. AC: Formal analysis; investigation; writing-review and editing. YH: Investigation; methodology; writing-review and editing. CTL: Investigation; methodology; writing-review and editing. DK: Investigation; methodology; writing-review and editing. BSZ: Funding acquisition; investigation; supervision; writing-review and editing. SFAG: Funding acquisition; investigation; supervision; writing-review and editing. JMJ: Funding acquisition; investigation; supervision; writing-review and editing. RDJ: Funding acquisition; investigation; supervision; writing-review and editing. MKE: Funding acquisition; investigation; supervision; writing-review and editing. TBH: Funding acquisition; investigation; supervision; writing-review and editing. JMZ: Conceptualization; funding acquisition; investigation; methodology; supervision; writing-review and editing. DK: Conceptualization; funding acquisition; investigation; methodology; supervision; writing-review and editing. Funding sources include NIAMS R01‐AR041398, 5‐P60‐AR30701, R01‐AR049747, R01‐AR051124, 5‐P60‐AR49465, and 5‐P60‐AR062760; NIA T32‐AG023480 and R01‐AG033618; CDC/ASPPH S043, S1734, and S3486; CDC U01DP003206 and U01DP006266; and Algynomics, Inc. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C.

Funders	Funder number
Algynomics, Inc.
US Department of Health and Human Services
National Institutes of Health
U.S. Department of Health and Human Services	HHSN268201600002C, HHSN268201600003C, HHSN268201600001C, HHSN268201600018C, HHSN268201600004C
National Institute on Aging	CDC/ASPPH S043, S1734, U01DP003206, U01DP006266, R01-AG033618, T32-AG023480, S3486
National Heart, Lung, and Blood Institute	R01HL105756
National Institute of Arthritis and Musculoskeletal and Skin Diseases	5-P60-AR49465, 5-P60-AR062760, R01-AR041398, R01-AR051124, R01-AR049747, 5-P60-AR30701

Keywords

AFRICAN ANCESTRY POPULATION
BMD
DXA
GENERAL POPULATION STUDIES
GENETICS
GENETICS RESEARCH
HUMAN ASSOCIATION STUDIES
META-ANALYSIS
OSTEOPOROSIS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/jbmr.4220

Cite this

Yau, M. S., Kuipers, A. L., Price, R., Nicolas, A., Tajuddin, S. M., Handelman, S. K., Arbeeva, L., Chesi, A., Hsu, Y. H., Liu, C. T., Karasik, D., Zemel, B. S., Grant, S. F. A., Jordan, J. M., Jackson, R. D., Evans, M. K., Harris, T. B., Zmuda, J. M., & Kiel, D. P. (2021). A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations. Journal of Bone and Mineral Research, 36(3), 469-479. https://doi.org/10.1002/jbmr.4220

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title = "A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations",

abstract = "Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I2 index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10−4), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10−4) and 7q31 (WNT16, p = 2.96 × 10−5), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p < 2.23 × 10−4), 11q14 (DCDC5, p < 5.35 × 10−5), and 17p13 (SMG6, p < 6.78 × 10−5) that were not tagged by European ancestry index SNPs. Rare single-nucleotide variants in AKAP11 (p = 2.32 × 10−2), MBL2 (p = 4.09 × 10−2), MEPE (p = 3.15 × 10−2), SLC25A13 (p = 3.03 × 10−2), STARD3NL (p = 3.35 × 10−2), and TNFRSF11A (p = 3.18 × 10−3) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power and to identify both other loci that are transferable across populations and novel population-specific variants.",

keywords = "AFRICAN ANCESTRY POPULATION, BMD, DXA, GENERAL POPULATION STUDIES, GENETICS, GENETICS RESEARCH, HUMAN ASSOCIATION STUDIES, META-ANALYSIS, OSTEOPOROSIS",

author = "Yau, {Michelle S.} and Kuipers, {Allison L.} and Ryan Price and Aude Nicolas and Tajuddin, {Salman M.} and Handelman, {Samuel K.} and Liubov Arbeeva and Alessandra Chesi and Hsu, {Yi Hsiang} and Liu, {Ching Ti} and David Karasik and Zemel, {Babette S.} and Grant, {Struan F.A.} and Jordan, {Joanne M.} and Jackson, {Rebecca D.} and Evans, {Michele K.} and Harris, {Tamara B.} and Zmuda, {Joseph M.} and Kiel, {Douglas P.}",

note = "Publisher Copyright: {\textcopyright} 2020 American Society for Bone and Mineral Research (ASBMR)",

year = "2021",

month = mar,

doi = "10.1002/jbmr.4220",

language = "אנגלית",

volume = "36",

pages = "469--479",

journal = "Journal of Bone and Mineral Research",

issn = "0884-0431",

publisher = "Wiley-Blackwell",

number = "3",

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Yau, MS, Kuipers, AL, Price, R, Nicolas, A, Tajuddin, SM, Handelman, SK, Arbeeva, L, Chesi, A, Hsu, YH, Liu, CT, Karasik, D, Zemel, BS, Grant, SFA, Jordan, JM, Jackson, RD, Evans, MK, Harris, TB, Zmuda, JM & Kiel, DP 2021, 'A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations', Journal of Bone and Mineral Research, vol. 36, no. 3, pp. 469-479. https://doi.org/10.1002/jbmr.4220

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T1 - A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations

AU - Yau, Michelle S.

AU - Kuipers, Allison L.

AU - Price, Ryan

AU - Nicolas, Aude

AU - Tajuddin, Salman M.

AU - Handelman, Samuel K.

AU - Arbeeva, Liubov

AU - Chesi, Alessandra

AU - Hsu, Yi Hsiang

AU - Liu, Ching Ti

AU - Karasik, David

AU - Zemel, Babette S.

AU - Grant, Struan F.A.

AU - Jordan, Joanne M.

AU - Jackson, Rebecca D.

AU - Evans, Michele K.

AU - Harris, Tamara B.

AU - Zmuda, Joseph M.

AU - Kiel, Douglas P.

PY - 2021/3

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N2 - Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I2 index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10−4), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10−4) and 7q31 (WNT16, p = 2.96 × 10−5), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p < 2.23 × 10−4), 11q14 (DCDC5, p < 5.35 × 10−5), and 17p13 (SMG6, p < 6.78 × 10−5) that were not tagged by European ancestry index SNPs. Rare single-nucleotide variants in AKAP11 (p = 2.32 × 10−2), MBL2 (p = 4.09 × 10−2), MEPE (p = 3.15 × 10−2), SLC25A13 (p = 3.03 × 10−2), STARD3NL (p = 3.35 × 10−2), and TNFRSF11A (p = 3.18 × 10−3) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power and to identify both other loci that are transferable across populations and novel population-specific variants.

AB - Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I2 index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10−4), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10−4) and 7q31 (WNT16, p = 2.96 × 10−5), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p < 2.23 × 10−4), 11q14 (DCDC5, p < 5.35 × 10−5), and 17p13 (SMG6, p < 6.78 × 10−5) that were not tagged by European ancestry index SNPs. Rare single-nucleotide variants in AKAP11 (p = 2.32 × 10−2), MBL2 (p = 4.09 × 10−2), MEPE (p = 3.15 × 10−2), SLC25A13 (p = 3.03 × 10−2), STARD3NL (p = 3.35 × 10−2), and TNFRSF11A (p = 3.18 × 10−3) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power and to identify both other loci that are transferable across populations and novel population-specific variants.

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KW - BMD

KW - DXA

KW - GENERAL POPULATION STUDIES

KW - GENETICS

KW - GENETICS RESEARCH

KW - HUMAN ASSOCIATION STUDIES

KW - META-ANALYSIS

KW - OSTEOPOROSIS

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A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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