BA3 - Genome-wide Association Study to Identify Genetic Components of Hip Fracture

This page provides study documentation for BA03.  Note that the assay of samples is continued in BA18.  For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Rebecca Jackson, MD,


The consistent finding of genetic susceptibility suggests that there are germ line sequence variants in the human genome that predispose to various “diseases.” Single nucleotide polymorphisms (SNPs), the most common sequence variants, may be directly associated with disease risk by affecting the function and or expression of an implicated gene or indirectly associated with disease risk through linkage disequilibrium (LD) with a causal sequence variant. These risk-associated SNPs will have different allele frequencies in the disease population as compared to the normal population and can be detected using genetic association studies. The ability to detect such SNPs depends on the strength of association, the frequencies of the risk alleles, the sample size, and the selection of SNPs to be used in the study.
Selecting the appropriate SNPs in genetic association studies is a challenging task. In addition to the possibility that sequence variants in many genes of multiple biological pathways may modify disease risk, our ability to prioritize the SNPs based on their predicted functional effects is very limited (the candidate gene approach). Although the selection of SNPs in candidate genes has been a commonly used approach, a comprehensive screen for SNPs throughout the entire genome maybe a more rational alternative. Because it requires fewer a priori assumptions, a genome-wide approach may increase the likelihood of identifying risk variants and may reveal novel mechanisms.
Although the need for a genome-wide approach is well supported, such an approach was not practical until now. Several recently developed high-throughput genotyping methods make this approach possible. SNP arrays by Illumina, Affymetrix, and Perlegen are three existing platforms that have made large-scale, genome-wide SNP studies fully plausible. For example, two versions of the Illumina Infinium assay are available for genotyping 100,000 and 300,000 SNPs across the genome. Likewise, three versions of the Affymetrix GeneChip are available for genotyping 100,000, 250,000 or 500,000 SNPs across the genome.  Despite their recent introduction, these genome wide SNP genotyping technologies have already made an impact in the form of scientific publications and contribution to and validated against the International HapMap Project. These data suggest that these technologies are an efficient and reliable method for genome-wide SNP analysis.
The goal of this proposed study is to identify genetic alterations that make postmenopausal women susceptible to hip fracture, one of the most devastating fractures associated with osteoporosis in the United States. Previous studies have successfully identified some single gene mutations that are associated with either low bone density or other factors contributing to increased risk of fracture. However, these mutations are rare and are only directly related to a small proportion of osteoporotic fractures. Most osteoporotic fracture risk appears to be due, at least in part, to mutations that have low penetrance and high frequency in which one or more of these mutations are necessary for increase risk. One of the main goals of this study is to identify genetic alterations that contribute to fracture risk, particularly the common (minor allele frequency ≥ 5%) low-penetrance, low-risk genes that might affect risk by increasing or decreasing a person’s susceptibility to the osteoporosis-causing effects of environmental and lifestyle exposures.
The proposed project is consistent with the stated goals of the BAA to “maximize the scientific yield from the biologic resource and associated participant exposures and outcome data “. It will improve our knowledge about genetic predictors of osteoporotic fracture, one of the most common diseases affecting older women. Using innovative cutting-edge technology to address important scientific questions, the results will have substantial scientific and public health benefits.
The goal of this study is to identify genetic factors that contribute to risk for hip fracture through a genome-wide association study of postmenopausal women in the WHI, a prospective population-based, very large cohort of women not specifically chosen for their risk of osteoporosis. To date, there have been only limited studies that have examined candidate gene associations with hip fracture. The proposed study will be the first study to use a SNP-based genome scan to directly address hip fracture as a phenotype. The main focus of this study and main specific hypothesis that will be addressed is:
Primary aim:
1. To identify a reproducible set of SNPs that predicts the occurrence of hip fracture in postmenopausal women.
Secondary specific aims include:
2.  To determine whether the SNPs associated with hip fracture differ between fractures of the trochanter versus fractures of the femoral neck; and
3.  To determine whether the SNPs associated with hip fracture differ when the fracture occurs in younger postmenopausal women versus older postmenopausal women
In addition, we have defined one exploratory aim to test whether hip fracture-related SNPs are associated with the beneficial effects of hormone therapy or calcium plus vitamin D supplementation to determine whether subgroups of women can be identified who experienced greater or lesser benefit from these interventions in relation to hip fracture.