Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction (original) (raw)
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Cancer discovery, 2015
A genome-wide association study of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously-identified locus 6q25.3 that replicated in PEGASUS (N=7,539) and MEC (N=4,679) (p=1.0x10(-19), OR=1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (p=1.3x10(-23)) and SLC22A3 (p=3.2x10(-52)). At the known 19q13.33 locus rs2659124 (p=1.3x10(-13), OR=1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (p<1.0x10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic Whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained ~7.6% of disease heritability. The entire GWAS array explained ~33.4...
Genome-wide association study of prostate cancer identifies a second risk locus at …
Nature genetics, 2007
In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study (GWAS), with 1,047,986 single nucleotide polymorphism (SNP) markers examined in 3,425 African American prostate cancer cases and 3,290 African American male controls. The most significant 17 novel associations in stage 1 were followed-up in 1,844 cases and 3,269 controls of African ancestry. We identified a novel risk variant on chromosome 17q21 (rs7210100; odds ratio per allele=1.51; p=3.4×10 −13). The frequency of the risk allele is ~5% in men of African descent while it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting GWAS in diverse populations. Genome-wide association studies (GWAS) of prostate cancer have identified more than 30 risk associated variants, which in aggregate are estimated to account for approximately 20% of the familial risk of prostate cancer 1-12. Aside from admixture, and fine-mapping studies which identified multiple independent risk variants at 8q24 13,14 , and a more recent GWAS among Japanese men which identified five novel loci 9 , discoveries in prostate cancer have come from studies in men of European ancestry. However, prostate cancer incidence in men of African ancestry is greater than in non-African populations 15 , with the disparity presumably reflecting both differences in prevalence of environmental risk factors and susceptibility alleles that are shared among men of African descent. For example, the risk variants at 8q24, many of which are more common in men of African ancestry 14 , could contribute partly to the greater incidence of prostate cancer in this population, and provide some support for the hypothesis of a genetic contribution underlying racial/ethnic disparities in disease risk. Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Characterizing Genetic Risk at Known Prostate Cancer Susceptibility Loci in African Americans
PLOS Genetics, 2011
GWAS of prostate cancer have been remarkably successful in revealing common genetic variants and novel biological pathways that are linked with its etiology. A more complete understanding of inherited susceptibility to prostate cancer in the general population will come from continuing such discovery efforts and from testing known risk alleles in diverse racial and ethnic groups. In this large study of prostate cancer in African American men (3,425 prostate cancer cases and 3,290 controls), we tested 49 risk variants located in 28 genomic regions identified through GWAS in men of European and Asian descent, and we replicated associations (at p#0.05) with roughly half of these markers. Through fine-mapping, we identified nearby markers in many regions that better define associations in African Americans. At 8q24, we found 9 variants (p#6610 24 ) that best capture risk of prostate cancer in African Americans, many of which are more common in men of African than European descent. The markers found to be associated with risk at each locus improved risk modeling in African Americans (per allele OR = 1.17) over the alleles reported in the original GWAS (OR = 1.08). In summary, in this detailed analysis of the prostate cancer risk loci reported from GWAS, we have validated and improved upon markers of risk in some regions that better define the association with prostate cancer in African Americans. Our findings with variants at 8q24 also reinforce the importance of this region as a major risk locus for prostate cancer in men of African ancestry.
Multi-ethnic transcriptome-wide association study of prostate cancer
2020
The genetic risk for prostate cancer has been governed by a few rare variants with high penetrance and over 150 commonly occurring variants with lower impact on risk; however, most of these variants have been identified in studies containing exclusively European individuals. People of non-European ancestries make up less than 15% of prostate cancer GWAS subjects. Across the globe, incidence of prostate cancer varies with population due to environmental and genetic factors. The discrepancy between disease incidence and representation in genetics highlights the need for more studies of the genetic risk for prostate cancer across diverse populations. To better understand the genetic risk for prostate cancer across diverse populations, we performed PrediXcan and GWAS in a cohort of 4,769 self-identified African American (2,463 cases and 2,306 controls), 2,199 Japanese American (1,106 cases and 1,093 controls), and 2,147 Latin American (1,081 cases and 1,066 controls) individuals from th...
Nature Genetics, 2011
In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study (GWAS), with 1,047,986 single nucleotide polymorphism (SNP) markers examined in 3,425 African American prostate cancer cases and 3,290 African American male controls. The most significant 17 novel associations in stage 1 were followed-up in 1,844 cases and 3,269 controls of African ancestry. We identified a novel risk variant on chromosome 17q21 (rs7210100; odds ratio per allele=1.51; p=3.4×10 −13). The frequency of the risk allele is ~5% in men of African descent while it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting GWAS in diverse populations. Genome-wide association studies (GWAS) of prostate cancer have identified more than 30 risk associated variants, which in aggregate are estimated to account for approximately 20% of the familial risk of prostate cancer 1-12. Aside from admixture, and fine-mapping studies which identified multiple independent risk variants at 8q24 13,14 , and a more recent GWAS among Japanese men which identified five novel loci 9 , discoveries in prostate cancer have come from studies in men of European ancestry. However, prostate cancer incidence in men of African ancestry is greater than in non-African populations 15 , with the disparity presumably reflecting both differences in prevalence of environmental risk factors and susceptibility alleles that are shared among men of African descent. For example, the risk variants at 8q24, many of which are more common in men of African ancestry 14 , could contribute partly to the greater incidence of prostate cancer in this population, and provide some support for the hypothesis of a genetic contribution underlying racial/ethnic disparities in disease risk. Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
The Canadian journal of urology, 2008
Disparities in prostate cancer incidence and outcomes are a hallmark of the global pattern of prostate cancer, with men of African descent suffering disproportionately from this disease. The causes of these disparities are poorly understood. A review of the literature was undertaken to evaluate the role that genetic susceptibility may play in prostate cancer etiology and outcomes, with a particular emphasis on disparities. The genetic contribution to prostate cancer is well established, and a number of candidate prostate cancer genes have been identified. Significant differences in the frequency of risk alleles in these genes have been identified across the major races. These allele frequency differences may in part explain an increased susceptibility to prostate cancer in some populations. In addition, non-genetic factors contribute significantly to prostate cancer disparities, and the cumulative contribution of both genetic and non-genetic factors to poor-prognosis prostate cancer...
Clinical validity and utility of genetic risk scores in prostate cancer
Asian journal of andrology
Current issues related to prostate cancer (PCa) clinical care (e.g., over-screening, over-diagnosis, and over-treatment of nonaggressive PCa) call for risk assessment tools that can be combined with family history (FH) to stratify disease risk among men in the general population. Since 2007, genome-wide association studies (GWASs) have identified more than 100 SNPs associated with PCa susceptibility. In this review, we discuss (1) the validity of these PCa risk-associated SNPs, individually and collectively; (2) the various methods used for measuring the cumulative effect of multiple SNPs, including genetic risk score (GRS); (3) the adequate number of SNPs needed for risk assessment; (4) reclassification of risk based on evolving numbers of SNPs used to calculate genetic risk, (5) risk assessment for men from various racial groups, and (6) the clinical utility of genetic risk assessment. In conclusion, data available to date support the clinical validity of PCa risk-associated SNPs ...