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Freedman ML Reich D Penney KL McDonald GJ Mignault AA Patterson N Gabriel SB Topol EJ Smoller JW Pato CN Pato MT Petryshen TL Kolonel LN Lander ES Sklar P Henderson B Hirschhorn JN Altshuler D 《Nature genetics》2004,36(4):388-393
Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies. 相似文献
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Akamatsu S Takata R Haiman CA Takahashi A Inoue T Kubo M Furihata M Kamatani N Inazawa J Chen GK Le Marchand L Kolonel LN Katoh T Yamano Y Yamakado M Takahashi H Yamada H Egawa S Fujioka T Henderson BE Habuchi T Ogawa O Nakamura Y Nakagawa H 《Nature genetics》2012,44(4):426-9, S1
We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 × 10(-4)) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 × 10(-10); FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 × 10(-8)) and 3p11.2 (rs2055109; P = 3.94 × 10(-8)). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 × 10(-7)). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations. 相似文献
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de Bakker PI Burtt NP Graham RR Guiducci C Yelensky R Drake JA Bersaglieri T Penney KL Butler J Young S Onofrio RC Lyon HN Stram DO Haiman CA Freedman ML Zhu X Cooper R Groop L Kolonel LN Henderson BE Daly MJ Hirschhorn JN Altshuler D 《Nature genetics》2006,38(11):1298-1303
A general question for linkage disequilibrium-based association studies is how power to detect an association is compromised when tag SNPs are chosen from data in one population sample and then deployed in another sample. Specifically, it is important to know how well tags picked from the HapMap DNA samples capture the variation in other samples. To address this, we collected dense data uniformly across the four HapMap population samples and eleven other population samples. We picked tag SNPs using genotype data we collected in the HapMap samples and then evaluated the effective coverage of these tags in comparison to the entire set of common variants observed in the other samples. We simulated case-control association studies in the non-HapMap samples under a disease model of modest risk, and we observed little loss in power. These results demonstrate that the HapMap DNA samples can be used to select tags for genome-wide association studies in many samples around the world. 相似文献
4.
Stacey SN Manolescu A Sulem P Rafnar T Gudmundsson J Gudjonsson SA Masson G Jakobsdottir M Thorlacius S Helgason A Aben KK Strobbe LJ Albers-Akkers MT Swinkels DW Henderson BE Kolonel LN Le Marchand L Millastre E Andres R Godino J Garcia-Prats MD Polo E Tres A Mouy M Saemundsdottir J Backman VM Gudmundsson L Kristjansson K Bergthorsson JT Kostic J Frigge ML Geller F Gudbjartsson D Sigurdsson H Jonsdottir T Hrafnkelsson J Johannsson J Sveinsson T Myrdal G Grimsson HN Jonsson T von Holst S 《Nature genetics》2007,39(7):865-869
Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone. 相似文献
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Hinch AG Tandon A Patterson N Song Y Rohland N Palmer CD Chen GK Wang K Buxbaum SG Akylbekova EL Aldrich MC Ambrosone CB Amos C Bandera EV Berndt SI Bernstein L Blot WJ Bock CH Boerwinkle E Cai Q Caporaso N Casey G Cupples LA Deming SL Diver WR Divers J Fornage M Gillanders EM Glessner J Harris CC Hu JJ Ingles SA Isaacs W John EM Kao WH Keating B Kittles RA Kolonel LN Larkin E Le Marchand L McNeill LH Millikan RC Murphy A Musani S Neslund-Dudas C Nyante S Papanicolaou GJ Press MF Psaty BM 《Nature》2011,476(7359):170-175
Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P?value 10(-245)). We identify a 17-base-pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution. 相似文献
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Haiman CA Patterson N Freedman ML Myers SR Pike MC Waliszewska A Neubauer J Tandon A Schirmer C McDonald GJ Greenway SC Stram DO Le Marchand L Kolonel LN Frasco M Wong D Pooler LC Ardlie K Oakley-Girvan I Whittemore AS Cooney KA John EM Ingles SA Altshuler D Henderson BE Reich D 《Nature genetics》2007,39(5):638-644
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. 相似文献
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Easton DF Pooley KA Dunning AM Pharoah PD Thompson D Ballinger DG Struewing JP Morrison J Field H Luben R Wareham N Ahmed S Healey CS Bowman R;SEARCH collaborators Meyer KB Haiman CA Kolonel LK Henderson BE Le Marchand L Brennan P Sangrajrang S Gaborieau V Odefrey F Shen CY Wu PE Wang HC Eccles D Evans DG Peto J Fletcher O Johnson N Seal S Stratton MR Rahman N Chenevix-Trench G Bojesen SE Nordestgaard BG Axelsson CK Garcia-Closas M Brinton L Chanock S Lissowska J Peplonska B Nevanlinna H 《Nature》2007,447(7148):1087-1093
Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. 相似文献
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A common genetic risk factor for colorectal and prostate cancer 总被引:14,自引:0,他引:14
Haiman CA Le Marchand L Yamamato J Stram DO Sheng X Kolonel LN Wu AH Reich D Henderson BE 《Nature genetics》2007,39(8):954-956
Variants on chromosome 8q24 contribute risk for prostate cancer; here, we tested whether they also modulate risk for colorectal cancer. We studied 1,807 affected individuals and 5,511 controls and found that one variant, rs6983267, is also significantly associated with colorectal cancer (odds ratio = 1.22; P = 4.4 x 10(-6)) and that the apportionment of risk among the variants differs significantly between the two cancers. Comprehensive testing in the region uncovered variants capturing significant additional risk. Our results show that variants at 8q24 have different effects on cancer development that depend on the tissue type. 相似文献
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Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer
Stacey SN Manolescu A Sulem P Thorlacius S Gudjonsson SA Jonsson GF Jakobsdottir M Bergthorsson JT Gudmundsson J Aben KK Strobbe LJ Swinkels DW van Engelenburg KC Henderson BE Kolonel LN Le Marchand L Millastre E Andres R Saez B Lambea J Godino J Polo E Tres A Picelli S Rantala J Margolin S Jonsson T Sigurdsson H Jonsdottir T Hrafnkelsson J Johannsson J Sveinsson T Myrdal G Grimsson HN Sveinsdottir SG Alexiusdottir K Saemundsdottir J Sigurdsson A Kostic J Gudmundsson L Kristjansson K Masson G 《Nature genetics》2008,40(6):703-706
We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer. 相似文献
10.
Haiman CA Garcia RR Kolonel LN Henderson BE Wu AH Le Marchand L 《Nature genetics》2008,40(3):259-60; author reply 260-1
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