Genome-wide association study for femoral neck bone geometry

Abstract

Poor femoral neck bone geometry at the femur is an important risk factor for hip fracture. We conducted a genome-wide association study (GWAS) of femoral neck bone geometry, examining approximately 379,000 eligible single-nucleotide polymorphisms (SNPs) in 1000 Caucasians. A common genetic variant, rs7430431 in the receptor transporting protein 3 (RTP3) gene, was identified in strong association with the buckling ratio (BR, P = 1.6 x 10(-7)), an index of bone structural instability, and with femoral cortical thickness (CT, P = 1.9 x 10(-6)). The RTP3 gene is located in 3p21.31, a region that we found to be linked with CT (LOD = 2.19, P = 6.0 x 10(-4)) in 3998 individuals from 434 pedigrees. The replication analyses in 1488 independent Caucasians and 2118 Chinese confirmed the association of rs7430431 to BR and CT (combined P = 7.0 x 10(-3) for BR and P = 1.4 x 10(-2) for CT). In addition, 350 hip fracture patients and 350 healthy control individuals were genotyped to assess the association of the RTP3 gene with the risk of hip fracture. Significant association between a nearby common SNP, rs10514713 of the RTP3 gene, and hip fracture (P = 1.0 x 10(-3)) was found. Our observations suggest that RTP3 may be a novel candidate gene for femoral neck bone geometry.

Fig. 1

Schematic view of association results, marker density, and LD structure within and adjacent to the RTP3 gene. (A) Genome-wide association study (GWAS) results for both single-marker and LD-block haplotype (solid line) association results. The SNP rs7431430 achieved the most significant association with BR (P = 1.61 × 10⁻⁷). Block 3 achieved a highly suggestive association with BR (P = 5.76 × 10⁻⁵). RTP3 = receptor (chemosensory) transporter protein 3; LRRC2 = leucine-rich repeat containing 2; LTF = lactotransferrin; CCRL2 = chemokine (C-C motif) receptor-like 2; ALS2CL = ALS2 C-terminal like. (B) Gene structure and LD patterns for the 21 SNPs within or adjacent to the RTP3 gene in GWAS Caucasian samples. Exons are depicted with a vertical bar. Positions of the 21 SNPs (listed in Table 2) are sketched. LD block structure, as depicted by Haploview, is shown in the bottom frame. The increasing degree of darkness from white to black represents the increasing strength of LD (measured by r²).

Fig. 2

Least square means (± SE) of BR and CT values in the three genotypes of SNP rs7430431 in the unrelated GWAS Caucasian subjects. A linear regression model was used with age, age², sex, age/age²-by-sex interaction, height, and weight as covariates. P values of one-way ANOVA for testing the genotype effects on adjusted BR and CT are given.