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Study Description

This substudy phs000281 WHISP contains exome sequencing, produced as part of NHLBI's GO-ESP project. Summary level phenotypes for the WHI Cohort study participants can be viewed at the top-level study page phs000200 WHI Cohort. Individual level phenotype data and molecular data for all WHI top-level study and substudies are available by requesting Authorized Access to the WHI Cohort study phs000200.

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO.

Women's Health Initiative:

The Women's Health Initiative (WHI) is a long-term national health study that has focused on strategies for preventing heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. The original WHI study included 161,808 postmenopausal women enrolled between 1993 and 1998. The Fred Hutchinson Cancer Research Center in Seattle, WA serves as the WHI Clinical Coordinating Center for data collection, management, and analysis of the WHI.

The WHI has two major parts: a partial factorial randomized Clinical Trial (CT) and a longitudinal cohort Observational Study (OS); both were conducted at 40 Clinical Centers nationwide. The CT enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies. If eligible, women could choose to enroll in one, two, or all three of the trial components. The components are:

  • Hormone Therapy Trials (HT): This component examined the effects of combined hormones or estrogen alone on the prevention of coronary heart disease and osteoporotic fractures, and associated risk for breast cancer. Women participating in this component took hormone pills or a placebo (inactive pill) until the Estrogen plus Progestin and Estrogen Alone trials were stopped early in July 2002 and March 2004, respectively. All HT participants continued to be followed without intervention until close-out.
  • Dietary Modification Trial (DM): The Dietary Modification component evaluated the effect of a low-fat and high fruit, vegetable and grain diet on the prevention of breast and colorectal cancers and coronary heart disease. Study participants followed either their usual eating pattern or a low-fat dietary pattern.
  • Calcium/Vitamin D Trial (CaD): This component began 1 to 2 years after a woman joined one or both of the other clinical trial components. It evaluated the effect of calcium and vitamin D supplementation on the prevention of osteoporotic fractures and colorectal cancer. Women in this component took calcium and vitamin D pills or a placebo.
  • The Observational Study (OS) examines the relationship between lifestyle, health and risk factors and specific disease outcomes. This component involves tracking the medical history and health habits of 93,676 women. Recruitment for the observational study was completed in 1998 and participants were followed for 8 to 12 years. The original protocol allowed for follow-up until March 2005, after which participants were invited to enroll in the WHI Extension Study for follow-up through 2010. As of August 2009 there were 115,406 women enrolled in the WHI Extension Study.

WHI Sequencing Project (WHISP) / Exome Sequencing Project (ESP)

In 2010, genetic samples from WHI participants were sequenced for WHISP for inclusion in the dbGaP as part of the NHLBI GO Exome Sequencing Project (ESP). The goal of the NHLBI GO Exome Sequencing Project (ESP) is to discover novel genes and mechanisms contributing to heart, lung and blood disorders by pioneering the application of next-generation sequencing of the protein coding regions of the human genome across diverse, richly-phenotyped populations and to share these datasets and findings with the scientific community to extend and enrich the diagnosis, management and treatment of heart, lung and blood disorders.

Samples are being selected from both arms of the parent WHI study. WHISP will include sampling for case-control status in clinical outcomes, extreme tail sampling for quantitative traits, and random cohort sampling for a deeply phenotyped reference sample.

Authorized Access
Publicly Available Data (Public ftp)

Note: Access to publicly available data is available on the public ftp site for study phs000200.v9.p3.

Study Inclusion/Exclusion Criteria

Women's Health Initiative:
Women were eligible for WHI participation if they were between 50 and 79 years of age, postmenopausal, likely to live in the area for 3 years and have no condition predicting survival < 3 years. The WHI CT enrolled and randomized 68,132 women ages 50-79 into at least one of three clinical trials (hormone therapy; low fat dietary modification, calcium + vitamin D). The OS enrolled 93,676 women ages 50-79 into a parallel prospective cohort study. Population based enrollment occurred from 1993 to 1998 at 40 centers throughout the US. Exclusion criteria are listed in Table 1 of the Baseline Monograph paper (available at

WHISP participants are women enrolled in WHI who meet eligibility requirements for this study and eligibility for submission to dbGaP, and who provided DNA samples. Case selection of adjudicated phenotypes of interest will include participants representing either the tails of multiple phenotypic distributions for traits of interest for NHLBI or richly phenotyped individuals and through nested case-cohort studies for heart, lung and blood outcomes with a control group.

Details about the specific selected phenotypes, sample size, and sequencing method will be provided in collaboration with the ESP GO Steering Committee of groups funded through the same ARRA.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Exome Sequencing Illumina Genome Analyzer IIX N/A N/A
Exome Sequencing Illumina HiSeq 2000 N/A N/A
Study History

Women's Health Initiative:

  • October 1992 - Clinical Coordinating Center operations begin
  • March 1993 - 16 Clinical Centers selected
  • September 1993 - Recruitment of participants for 2 Hormone Therapy Trials (HT) trials and the Dietary Modification Trial (DM) begins
  • September 1994 - 24 additional Clinical Centers selected; Recruitment of participants for the Observational Study (OS) begins
  • June 1995 - CaD randomization begins
  • August 1998 - Randomization of participants for the DM ends
  • October 1998 - Randomization of participants for the HT ends
  • December 1998 - Recruitment of participants for the OS ends
  • September 2000 - Randomization of participants for the CaD ends
  • July 2002 - Estrogen plus Progestin HT was stopped early and main results published
  • March 2004 - Estrogen-Alone HT was stopped early
  • April 2004 - Main results of Estrogen-Alone HT published; Closeout of OS begins
  • October 2004 - Closeout of clinical trials (HT, DM, and CaD) begins
  • March 2005 - Study close-out ends
  • April 2005 - Extension study begins
  • September 2005 - Final WHI outcomes obtained and WHI database closed
  • February 2006 - Main results of DM and CaD published
  • September 2010 - Extension study scheduled to close

Selected publications
Diseases/Traits Related to Study (MESH terms)
Authorized Data Access Requests
Study Attribution