Genome-wide association study of bone mineral density in premenopausal European-American women and replication in African-American women

Abstract

Context: Several genome-wide association studies (GWAS) have been performed to identify genes contributing to bone mineral density (BMD), typically in samples of elderly women and men.

Objective: The objective of the study was to identify genes contributing to BMD in premenopausal women.

Design: GWAS using the Illumina 610Quad array in premenopausal European-American (EA) women and replication of the top 50 single-nucleotide polymorphisms (SNPs) for two BMD measures in African-American (AA) women.

Subjects: Subjects included 1524 premenopausal EA women aged 20-45 yr from 762 sibships and 669 AA premenopausal women aged 20-44 yr from 383 sibships.

Interventions: There were no interventions.

Main outcome measures: BMD was measured at the lumbar spine and femoral neck by dual-energy x-ray absorptiometry. Age- and weight-adjusted BMD values were tested for association with each SNP, with P values determined by permutation.

Results: SNPs in CATSPERB on chromosome 14 provided evidence of association with femoral neck BMD (rs1298989, P = 2.7 x 10(-5); rs1285635, P = 3.0 x 10(-5)) in the EA women, and some supporting evidence was also observed with these SNPs in the AA women (rs1285635, P = 0.003). Genes identified in other BMD GWAS studies, including IBSP and ADAMTS18, were also among the most significant findings in our GWAS.

Conclusions: Evidence of association to several novel loci was detected in a GWAS of premenopausal EA women, and SNPs in one of these loci also provided supporting evidence in a sample of AA women.

Figure 1

Q-Q plot illustrating the relationship between the observed (black symbols) permutation-based association results (y-axis) and results expected for a GWAS study with the same properties (gray symbols) under the null hypothesis (x-axis). Minus log₁₀ P values are plotted on both axes.

Figure 2

Association results with lumbar spine (plus symbol) and femoral neck BMD (diamond symbol) in the AA women for additional SNPs in the 3′ region of the CATSPERB gene on chromosome 14. SNP rs1285635, identified in the GWAS and also demonstrating evidence of association in AA women, is indicated with the small circle.

Figure 3

Femoral neck BMD association results with SNPs in and near the ADAMTS18 locus on chromosome. Position and orientation of the gene are indicated by the black arrow.