A Multiethnic GWAS of Prostate Cancer

Multiple GWA studies of prostate cancer conducted in European White populations are ongoing. These studies will continue to have a dramatic impact on our understanding of the contribution of common genetic variation on inter-individual susceptibility to this common cancer. Important questions that will remain unanswered, however, are whether all common risk alleles for prostate cancer will be revealed in studies limited to populations of European ancestry. A comprehensive examination of common genetic variation in men of Japanese, Latino, and African ancestry will be required to understand population differences in disease risk and to reveal the full spectrum of causal alleles that exist in these populations. Further, genetic and environmental diversity is likely to contribute to ethnic heterogeneity of genetic effects. Elucidating gene x gene and gene x environment interactions is also likely to provide knowledge that may be critical for understanding the contribution of genetic susceptibility to racial/ethnic disparities in prostate cancer incidence and for translating the findings from GWA studies into interventions. In this study we plan to undertake a genome-wide association study (GWAS) of prostate cancer in the Multiethnic Cohort (MEC) Study. We propose the following hypotheses: (a) that inherited DNA variation influences risk of prostate cancer; (b) that many of the causal alleles will be outside known "candidate genes" requiring an agnostic, comprehensive search; and (c) that performing this search in a multi-ethnic cohort is more powerful than a study limited to a single population to reveal the full range of causal alleles relevant to the U.S. population. The version 1 release of this dataset will include genotype data for the Japanese and Latino populations in the study. The version 2 release will include data for the African ancestry population along with the Japanese and Latino subjects. The version 3 release will include fully-cleaned genotype data for all three populations. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to prostate cancer through large-scale genome-wide association studies of a well-characterized multi-ethnic cohort. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center and at the University of Southern California. Data cleaning and harmonization were performed at the GEI-funded GENEVA Coordinating Center at the University of Washington. As an add-on to this GWAS we performed a targeted re-sequencing of all known prostate cancer risk loci in the samples from the MEC. Sequencing was performed in Dr. Reich's lab at Harvard Medical School.]]> Informed ConsentThe Hawaii and Los Angeles Cancer Research Survey Prostate cancer cases have an invasive prostate cancer diagnosis after (incident) entry into cohort Controls were matched to cases on race/ethnicity, area of residence (California or Hawaii) and age at entry into cohort. Subjects were excluded from control selection if a prevalent (before entry to cohort) diagnosis of prostate cancer was reported on the baseline questionnaire or from the tumor registry. ]]> The Multiethnic Cohort (MEC) is a prospective study designed to investigate the association of diet, lifestyle, and genetic factors with the incidence of cancer and other chronic diseases. In 1993-1996, more than 215,000 men and women (aged 45 to 75 years at recruitment) entered the cohort by completing a 26-page mailed questionnaire that contained a quantitative food frequency questionnaire (FFQ) and information on demographic factors, personal behaviors, prior medical conditions, use of medications, family history of common cancers, and for women, reproductive history and use of hormone therapy. Participants are mainly from five self-reported racial/ethnic populations living in Hawaii and California: African Americans, Native Hawaiians, Japanese Americans, Latinos, and Whites. Incident cases of cancer are identified by annual linkage to the SEER cancer registries in California and Hawaii.]]>