Multiple regions within 8q24 independently affect risk for prostate cancer
Open accessAbstract
After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.
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In many standard GWA studies, multiple regression models have been used to pinpoint probable causal variants within genomic regions containing numerous associated variants.
“Multiple regression models have been applied in many standard GWA studies in an effort to identify the most likely causal variants in a particular genomic region harboring many associated variants72, 73.”
From Statistical analysis strategies for association studies involving rare variants (2010) · cites this paper as [72]
Because allele frequencies vary across human populations, the relative roles of common susceptibility genes can vary among ethnic groups; the 8q24 prostate cancer contribution is greater in African Americans because risk alleles occur at higher frequencies, not because they confer greater susceptibility.
“7) Because allele frequencies vary across human populations, the relative roles of common susceptibility genes can vary among ethnic groups. One example is the association of prostate cancer at 8q24: SNPs in the region play a role in all ethnic groups, but the contribution is greater in African Americans. This is not because the risk alleles yet found confer greater susceptibility in African”
From Genetic Mapping in Human Disease (2008) · cites this paper as [92]
A single locus can contain multiple independent common risk variants; for example, seven independent alleles at 8q24 for prostate cancer, three at CFH for AMD, three at IRF5 for SLE, and two at IL23R for Crohn's disease.
“5) A single locus can contain multiple independent common risk variants. Intensive study has already identified seven independent alleles at 8q24 for prostate cancer (92), three at complement factor H (CFH) for age-related macular degeneration (93, 94), three at IRF5 for systemic lupus erythematosus (95), and two at IL23R for Crohn’s disease (96).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [92]
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Self-citation
- Authors
- Haiman, C. A., Patterson, N., Freedman, M. L., Myers, S. R., Pike, M. C., Waliszewska, A., Neubauer, J., Tandon, A., Schirmer, C., McDonald, G. J., Greenway, S. C., Stram, D. O., Le Marchand, L., Kolonel, L. N., Frasco, M., Wong, D., Pooler, L. C., Ardlie, K., Oakley-Girvan, I., Whittemore, A. S., Cooney, K. A., John, E. M., Ingles, S. A., Altshuler, D., Henderson, B. E., & Reich, D.
- Affiliations
- University of Southern California (US)
- Broad Institute (US)
- Harvard University (US)
- University of Hawaiʻi at Mānoa (US)
- Cancer Prevention Institute of California (US)
- Stanford Medicine (US)
- University of Michigan (US)
- Corresponding author
- Reich, David
- ORCID
- Haiman, Christopher A
- Patterson, Nick
- Freedman, Matthew L
- Myers, Simon R
- Pike, Malcolm C
- Neubauer, Julie
- Greenway, Steven C
- Stram, Daniel O
- Kolonel, Laurence N
- Frasco, Melissa
- Pooler, Loreall C
- Ardlie, Kristin
- Oakley-Girvan, Ingrid
- Whittemore, Alice S
- Cooney, Kathleen A
- John, Esther M
- Ingles, Sue A
- Altshuler, David
- Reich, David
- Venue
- Nature Genetics
- Published
- 2007-04-01
- Volume
- 39
- Issue
- 5
- Pages
- 638-644
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2638766
- OpenAlex
- W2044916117
- Cited by
- 663
- References
- 19
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 9 · 2023: 21 · 2022: 7 · 2021: 18 · 2020: 22 · 2019: 14 · 2018: 12 · 2017: 24 · 2016: 17 · 2015: 27 · 2014: 40 · 2013: 33 · 2012: 43
- FWCI
- 54.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust
- National Institutes of Health
- National Human Genome Research Institute (K01HG002758, HG02758)
- National Cancer Institute (CA 69568, CA63464, U01CA063464, R37CA054281, CA79596, CA67044, R01CA067044, R01CA079596, R01CA054281, R01CA084979, R01CA063464, CA 54281, P50CA069568, U01CA067044, CA84979)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD00850, K12HD000850)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- prostate cancer, 8q24, genetic susceptibility, single nucleotide polymorphisms, risk alleles, cancer risk prediction, genetic association, non-coding variants
- MeSH terms
- Black or African American, Chromosomes, Human, Pair 8, Ethnicity, Genotype, Haplotypes, Humans, Male, Prostatic Neoplasms, Risk Factors, United States, Genetic Variation, Odds Ratio, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genomics, White People
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