|Grant Number:||5R01CA165862-02 Interpret this number|
|Primary Investigator:||Haiman, Christopher|
|Organization:||University Of Southern California|
|Project Title:||Genome-Wide Sequencing of Prostate Cancer in Men of African Ancestry|
DESCRIPTION (provided by applicant): African American men have two times or more the incidence rate of prostate cancer than other U.S. populations, and high rates of prostate cancer are also seen in other African and African-derived populations. It is generally accepted that both common and rare genetic variants contribute to risk of complex diseases such as prostate cancer, however their relative contributions to overall heritability is a subject of intense controversy. For rare variants to have a significant influence on the risk of complex disease the spectrum of effect sizes must be considerably larger in magnitude than for common variants; to date however there is only limited evidence for or against this hypothesis since the means of comprehensively testing rare variation in the genome has not been possible until very recently. In this proposal we seek to test the contributions of both common and rare genetic variants to the risk of prostate cancer in men of American ancestry using a targeted genome-wide association study approach. In Aim 1 we plan to sequence (at 30x coverage) the exome and regulatory regions (~160 Mb) of the genome, as defined by epigenetic marks in prostate cancer cell lines, in 1,000 men of African ancestry (500 with aggressive disease) and 1,000 controls. Both single SNP and burden of rare variants analyses will be performed and replication testing of the most statistically significant sequence variations (~24,000) will be examined in additional samples of African ancestry (6,000 cases and 6,000 controls) through the African Ancestry Prostate Cancer (AAPC) consortium. In addition to association testing of single variants, we will conduct "burden of rare variants analyses" of coding and non-coding variants at the gene and pathway level. In Aim 2, we will examine interactions between associated variants, environmental factors (thereby better defining the role of these factors) and disease severity. In Aim 3, we will assess biological function of the novel risk alleles identified in Aim 1 using a staged approach of eQTL analysis followed by in vitro analyses of enhancer activity as well as allele-specific effects. This proposal spans the spectrum of genetic epidemiologic research in prostate cancer, from genetic discovery (for all prostate cancer as well as aggressive disease) to gene environment interaction testing, to biological understanding. We expect this work to significantly advance knowledge of the etiology of prostate cancer and racial/ethnic disparities in prostate cancer risk, and to guide the development of future preventive, early detection, prognostic and even therapeutic measures.
Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults.
Authors: Chen F, He J, Zhang J, Chen GK, Thomas V, Ambrosone CB, Bandera EV, Berndt SI, Bernstein L, Blot WJ, Cai Q, Carpten J, Casey G, Chanock SJ, Cheng I, Chu L, Deming SL, Driver WR, Goodman P, Hayes RB, Hennis AJ, Hsing AW, Hu JJ, Ingles SA, John EM, Kittles RA, Kolb S, Leske MC, Millikan RC, Monroe KR, Murphy A, Nemesure B, Neslund-Dudas C, Nyante S, Ostrander EA, Press MF, Rodriguez-Gil JL, Rybicki BA, Schumacher F, Stanford JL, Signorello LB, Strom SS, Stevens V, Van Den Berg D, Wang Z, Witte JS, Wu SY, Yamamura Y, Zheng W, Ziegler RG, Stram AH, Kolonel LN, Le Marchand L, Henderson BE, Haiman CA, Stram DO
Source: PLoS One, 2015;10(6), p. e0131106.
EPub date: 2015 Jun 30.
The role of local ancestry adjustment in association studies using admixed populations.
Authors: Zhang J, Stram DO
Source: Genet Epidemiol, 2014 Sep;38(6), p. 502-15.
EPub date: 2014 Jul 15.
Ancestry informative marker panels for African Americans based on subsets of commercially available SNP arrays.
Authors: Tandon A, Patterson N, Reich D
Source: Genet Epidemiol, 2011 Jan;35(1), p. 80-3.