Bivariate genome-wide association analyses identified genes with pleiotropic effects for femoral neck bone geometry and age at menarche

Abstract

Femoral neck geometric parameters (FNGPs), which include cortical thickness (CT), periosteal diameter (W), buckling ratio (BR), cross-sectional area (CSA), and section modulus (Z), contribute to bone strength and may predict hip fracture risk. Age at menarche (AAM) is an important risk factor for osteoporosis and bone fractures in women. Some FNGPs are genetically correlated with AAM. In this study, we performed a bivariate genome-wide association study (GWAS) to identify new candidate genes responsible for both FNGPs and AAM. In the discovery stage, we tested 760,794 SNPs in 1,728 unrelated Caucasian subject, followed by replication analyses in independent samples of US Caucasians (with 501 subjects) and Chinese (with 826 subjects). We found six SNPs that were associated with FNGPs and AAM. These SNPs are located in three genes (i.e. NRCAM, IDS and LOC148145), suggesting these three genes may co-regulate FNGPs and AAM. Our findings may help improve the understanding of genetic architecture and pathophysiological mechanisms underlying both osteoporosis and AAM.

Figure 1. Comparison of statistical power of bivariate vs. univariate association analyses in three samples of this study.

The Y axis shows the expected power, and the X axis shows the heritability. Type 1 error was set at 0.05 and minor allele frequency (MAF) was set at 0.1. The sample sizes were 1728 (discovery Caucasians), 826 (replication Chinese) and 501 (replication Caucasians), respectively.

Figure 2. LD structure of the NRCAM gene in the discovery Caucasian sample.

The region demarcated in red indicates that r²>0.9. The region includes only one LD block as indicated by triangle with black lines. SNP rs6975557 and rs13230316 are located within one block.

Figure 3. LD structure of the upstream of LOC148145 gene in the discovery Caucasian sample.

The region demarcated in red indicates that r²>0.9. The region includes two LD blocks (Block1 and Block2) marked by triangles with black lines. SNPs rs8113142 and rs4141232 are located in Block1, and the SNP rs4805257 is located in Block 2.