A meta‐analysis of the transferability of bone mineral density genetic loci associations from European to African ancestry populations

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

Affiliations

¹Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA

²Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

³Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA

⁴Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA

⁵Laboratory of Epidemiology and Population Sciences, National Institute on Agingi, Baltimore, MD, USA

⁶Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

⁷Thurston Arthritis Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

⁸Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

⁹Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

¹⁰Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

¹¹Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel

¹²Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

¹³Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

¹⁴Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

¹⁵Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

Abstract and keywords

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 ⁻⁴), 11q14 (DCDC5, p ⁻⁵), and 17p13 (SMG6, p ⁻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: GENETICS RESEARCH; HUMAN ASSOCIATION STUDIES; GENERAL POPULATION STUDIES; OSTEOPOROSIS; BMD; GENETICS; AFRICAN ANCESTRY POPULATION; DXA; META‐ANALYSIS

Links

DOI: 10.1002/jbmr.4220

PubMed: 33249669

WoS: 000599748300001

History

Received: 2020-04-24

Revised: 2020-11-9

Accepted: 2020-11-19

Online: 2020-12-18

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