Fueled by the decreased costs of genotyping technologies, over the last couple of years many genome-wide association studies have reported associations of genetic variants with complex diseases and traits, such as cardiovascular diseases, cancer, diabetes, and obesity. As many of these associations have been repeatedly confirmed in large studies, we can consider them """"""""putative genuine variants"""""""". However, before these genes can be put to clinical use, important questions need to be answered, including how these genes interact with the environment, how their risk differs in disease subtypes and ethnical groups, and how they impact intermediate phenotypes. To fully examine the profile or """"""""epidemiologic architecture"""""""" we will comprehensively evaluate such putative genuine variants in the Women's Health Initiative (WHI) Clinical Trial (CT) (n=68,132) and Observational Study (OS) (n=93,676). The WHI is one of the most definitive, far reaching population-based trials of post-menopausal women's health ever undertaken. This large study population not only enables us to examine the population incidence for racial and ethnic subgroups and associated risks of rigorously defined, incident diseases (specific aim 1) but allows us to investigate associated risks given in-depth information on various environmental exposures and disease risk factors as well as three randomized interventions (hormone therapy;low-fat dietary modification;calcium + vitamin D supplements) (specific aim 2). The prospective and longitudinal collection of biospecimens, intermediate outcomes, and phenotypic characteristics, such as bone mineral density, hormone concentrations, breast density, or inflammation will further permit us to link genetic variants to relevant intermediate phenotypes, which will potentially provide important clues to the biological basis of the genuine associations (specific aim 3). For a variety of outcomes we will genotype within this 4-year project 72,000 participants for about 50 disease-specific putative genuine variants and 50 ancestral informative markers. Information generated from this study will be critical to determine the health impact of any given undisputable variant. Findings may also provide valuable insights into disease pathways and mechanisms, and targets for disease screening, prevention, and treatment. To facilitate a rapid utilization of these findings we will share results from this study with the scientific community and invite outside investigators to utilize the WHI resources.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHG1-HGR-M (M1))
Program Officer
Hindorff, Lucia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Avery, Christy L; Wassel, Christina L; Richard, Melissa A et al. (2017) Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations. Heart Rhythm 14:572-580
Justice, Anne E (see original citation for additional authors) (2017) Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits. Nat Commun 8:14977
Yoneyama, S; Yao, J; Guo, X et al. (2017) Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations. Int J Obes (Lond) 41:324-331
Zubair, Niha; Graff, Mariaelisa; Luis Ambite, Jose et al. (2016) Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci. Hum Mol Genet 25:5500-5512
Pei, Yu-Fang; Tian, Qing; Zhang, Lei et al. (2016) Exploring the Major Sources and Extent of Heterogeneity in a Genome-Wide Association Meta-Analysis. Ann Hum Genet 80:113-22
Polimanti, Renato; Kranzler, Henry R; Gelernter, Joel (2016) Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women. Neuropsychopharmacology 41:2688-96
Niu, Tianhua; Liu, Ning; Yu, Xun et al. (2016) Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies. J Bone Miner Res 31:358-68
Niu, Tianhua; Liu, Ning; Zhao, Ming et al. (2015) Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies. Hum Mol Genet 24:4710-27
Liu, Yao-Zhong; Zhou, Yu; Zhang, Lei et al. (2015) Attenuated monocyte apoptosis, a new mechanism for osteoporosis suggested by a transcriptome-wide expression study of monocytes. PLoS One 10:e0116792
Kocarnik, Jonathan M; Park, S Lani; Han, Jiali et al. (2015) Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the population architecture using genomics and epidemiology (PAGE) study. PLoS One 10:e0120491

Showing the most recent 10 out of 62 publications