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1.  A Method for Detecting Long Non-Coding RNAs with Tiled RNA Expression Microarrays 
PLoS ONE  2014;9(6):e99899.
Long non-coding ribonucleic acids (lncRNAs) have been proposed as biomarkers in prostate cancer. This paper proposes a selection method which uses data from tiled microarrays to identify relatively long regions of moderate expression independent of the microarray platform and probe design. The method is used to search for candidate long non-coding ribonucleic acids (lncRNAs) at locus 8q24 and is run on three independent experiments which all use samples from prostate cancer patients. The robustness of the method is tested by utilizing repeated copies of tiled probes. The method shows high consistency between experiments that used the same samples, but different probe layout. There also is statistically significant consistency when comparing experiments with different samples. The method selected the long non-coding ribonucleic acid PCNCR1 in all three experiments.
doi:10.1371/journal.pone.0099899
PMCID: PMC4061049  PMID: 24937006
2.  Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma 
Human Molecular Genetics  2014;23(11):3045-3053.
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 × 10−17, OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 × 10−13, OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.
doi:10.1093/hmg/ddt671
PMCID: PMC4014188  PMID: 24403052
3.  A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer 
Nature genetics  2012;44(12):1326-1329.
Western countries, prostate cancer is the most prevalent cancer of men, and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. In the present study we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. One variant was found to be associated with prostate cancer in European populations: rs188140481[A] (OR = 2.90, Pcomb = 6.2×10−34) located on 8q24, with an average risk allele control frequency of 0.54%. This variant is only very weakly correlated (r2 ≤ 0.06) with previously reported risk variants on 8q24, and remains significant after adjustment for all of them. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for the previously described HOXB13 mutation (rs138213197[T]), confirming it as prostate cancer risk variant in populations from all over Europe.
doi:10.1038/ng.2437
PMCID: PMC3562711  PMID: 23104005
4.  Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations 
Nature genetics  2009;41(4):460-464.
In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 × 10−27) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 × 10−9). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T4) and high concentration of triiodothyronine (T3).
doi:10.1038/ng.339
PMCID: PMC3664837  PMID: 19198613
5.  Discovery of common variants associated with low TSH levels and thyroid cancer risk 
Nature genetics  2012;44(3):319-322.
To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10−8 in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; Pcombined = 1.3 × 10−9), rs2439302 on 8p12 (OR = 1.36; Pcombined = 2.0 × 10−9) and rs116909374 on 14q13.3 (OR = 2.09; Pcombined = 4.6 × 10−11), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10−91) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.
doi:10.1038/ng.1046
PMCID: PMC3655412  PMID: 22267200
6.  Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer 
Gudmundsson, Julius | Sulem, Patrick | Rafnar, Thorunn | Bergthorsson, Jon T | Manolescu, Andrei | Gudbjartsson, Daniel | Agnarsson, Bjarni A | Sigurdsson, Asgeir | Benediktsdottir, Kristrun R | Blondal, Thorarinn | Jakobsdottir, Margret | Stacey, Simon N | Kostic, Jelena | Kristinsson, Kari T | Birgisdottir, Birgitta | Ghosh, Shyamali | Magnusdottir, Droplaug N | Thorlacius, Steinunn | Thorleifsson, Gudmar | Zheng, S Lilly | Sun, Jielin | Chang, Bao-Li | Elmore, J Bradford | Breyer, Joan P | McReynolds, Kate M | Bradley, Kevin M | Yaspan, Brian L | Wiklund, Fredrik | Stattin, Par | Lindström, Sara | Adami, Hans-Olov | McDonnell, Shannon K | Schaid, Daniel J | Cunningham, Julie M | Wang, Liang | Cerhan, James R | St Sauver, Jennifer L | Isaacs, Sara D | Wiley, Kathleen E | Partin, Alan W | Walsh, Patrick C | Polo, Sonia | Ruiz-Echarri, Manuel | Navarrete, Sebastian | Fuertes, Fernando | Saez, Berta | Godino, Javier | Weijerman, Philip C | Swinkels, Dorine W | Aben, Katja K | Witjes, J Alfred | Suarez, Brian K | Helfand, Brian T | Frigge, Michael L | Kristjansson, Kristleifur | Ober, Carole | Jonsson, Eirikur | Einarsson, Gudmundur V | Xu, Jianfeng | Gronberg, Henrik | Smith, Jeffrey R | Thibodeau, Stephen N | Isaacs, William B | Catalona, William J | Mayordomo, Jose I | Kiemeney, Lambertus A | Barkardottir, Rosa B | Gulcher, Jeffrey R | Thorsteinsdottir, Unnur | Kong, Augustine | Stefansson, Kari
Nature genetics  2008;40(3):281-283.
We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 × 10−13 and 7.7 × 10−9, respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.
doi:10.1038/ng.89
PMCID: PMC3598012  PMID: 18264098
7.  Genetic correction of PSA values using sequence variants associated with PSA levels 
Science translational medicine  2010;2(62):62ra92.
Measuring serum levels of the prostate specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. In order to search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and SNPs at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 (rs17632542 (KLK3: I179T), each with Pcombined < 3×10−10. Among 3,834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (OR between 1.15 and 1.27). Assessment of association between the 6 loci and prostate cancer risk in 5,325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the US showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other 4 loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.
doi:10.1126/scitranslmed.3001513
PMCID: PMC3564581  PMID: 21160077
8.  Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility 
Nature genetics  2009;41(10):1122-1126.
We report a genome-wide association follow up study on prostate cancer. We identify four variants associated with the disease in European populations: rs10934853-A (OR = 1.12, P = 2.9×10−10) on 3q21.3, two moderately correlated (r2 = 0.07) variants on 8q24.21; rs16902094-G (OR = 1.21, P = 6.2×10−15) and rs445114-T (OR = 1.14, P = 4.7×10−10) and rs8102476-C (OR = 1.12, P = 1.6×10−11) on 19q13.2. We also refine a previous association signal on 11q13 with the SNP rs11228565-A (OR =1.23, P = 6.7 × 10−12). In a multi-variant analysis, using 22 prostate cancer risk variants typed in the Icelandic population, we estimate that carriers belonging to the top 1.3% of the risk distribution have a risk of developing the disease that is more than 2.5 times greater than the population average risk estimates.
doi:10.1038/ng.448
PMCID: PMC3562712  PMID: 19767754
9.  European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene 
Rafnar, Thorunn | Vermeulen, Sita H. | Sulem, Patrick | Thorleifsson, Gudmar | Aben, Katja K. | Witjes, J. Alfred | Grotenhuis, Anne J. | Verhaegh, Gerald W. | Hulsbergen-van de Kaa, Christina A. | Besenbacher, Soren | Gudbjartsson, Daniel | Stacey, Simon N. | Gudmundsson, Julius | Johannsdottir, Hrefna | Bjarnason, Hjordis | Zanon, Carlo | Helgadottir, Hafdis | Jonasson, Jon Gunnlaugur | Tryggvadottir, Laufey | Jonsson, Eirikur | Geirsson, Gudmundur | Nikulasson, Sigfus | Petursdottir, Vigdis | Bishop, D. Timothy | Chung-Sak, Sei | Choudhury, Ananya | Elliott, Faye | Barrett, Jennifer H. | Knowles, Margaret A. | de Verdier, Petra J. | Ryk, Charlotta | Lindblom, Annika | Rudnai, Peter | Gurzau, Eugene | Koppova, Kvetoslava | Vineis, Paolo | Polidoro, Silvia | Guarrera, Simonetta | Sacerdote, Carlotta | Panadero, Angeles | Sanz-Velez, José I. | Sanchez, Manuel | Valdivia, Gabriel | Garcia-Prats, Maria D. | Hengstler, Jan G. | Selinski, Silvia | Gerullis, Holger | Ovsiannikov, Daniel | Khezri, Abdolaziz | Aminsharifi, Alireza | Malekzadeh, Mahyar | van den Berg, Leonard H. | Ophoff, Roel A. | Veldink, Jan H. | Zeegers, Maurice P. | Kellen, Eliane | Fostinelli, Jacopo | Andreoli, Daniele | Arici, Cecilia | Porru, Stefano | Buntinx, Frank | Ghaderi, Abbas | Golka, Klaus | Mayordomo, José I. | Matullo, Giuseppe | Kumar, Rajiv | Steineck, Gunnar | Kiltie, Anne E. | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari | Kiemeney, Lambertus A.
Human Molecular Genetics  2011;20(21):4268-4281.
Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10−11. SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the ‘urogenous contact hypothesis’ that urine production and voiding frequency modify the risk of UBC.
doi:10.1093/hmg/ddr303
PMCID: PMC3188988  PMID: 21750109
10.  A germline variant in the TP53 polyadenylation signal confers cancer susceptibility 
Stacey, Simon N | Sulem, Patrick | Jonasdottir, Aslaug | Masson, Gisli | Gudmundsson, Julius | Gudbjartsson, Daniel F | Magnusson, Olafur T | Gudjonsson, Sigurjon A | Sigurgeirsson, Bardur | Thorisdottir, Kristin | Ragnarsson, Rafn | Benediktsdottir, Kristrun R | Nexø, Bjørn A | Tjønneland, Anne | Overvad, Kim | Rudnai, Peter | Gurzau, Eugene | Koppova, Kvetoslava | Hemminki, Kari | Corredera, Cristina | Fuentelsaz, Victoria | Grasa, Pilar | Navarrete, Sebastian | Fuertes, Fernando | García-Prats, Maria D | Sanambrosio, Enrique | Panadero, Angeles | De Juan, Ana | Garcia, Almudena | Rivera, Fernando | Planelles, Dolores | Soriano, Virtudes | Requena, Celia | Aben, Katja K | van Rossum, Michelle M | Cremers, Ruben G H M | van Oort, Inge M | van Spronsen, Dick-Johan | Schalken, Jack A | Peters, Wilbert H M | Helfand, Brian T | Donovan, Jenny L | Hamdy, Freddie C | Badescu, Daniel | Codreanu, Ovidiu | Jinga, Mariana | Csiki, Irma E | Constantinescu, Vali | Badea, Paula | Mates, Ioan N | Dinu, Daniela E | Constantin, Adrian | Mates, Dana | Kristjansdottir, Sjofn | Agnarsson, Bjarni A | Jonsson, Eirikur | Barkardottir, Rosa B | Einarsson, Gudmundur V | Sigurdsson, Fridbjorn | Moller, Pall H | Stefansson, Tryggvi | Valdimarsson, Trausti | Johannsson, Oskar T | Sigurdsson, Helgi | Jonsson, Thorvaldur | Jonasson, Jon G | Tryggvadottir, Laufey | Rice, Terri | Hansen, Helen M | Xiao, Yuanyuan | Lachance, Daniel H | O’Neill, Brian Patrick | Kosel, Matthew L | Decker, Paul A | Thorleifsson, Gudmar | Johannsdottir, Hrefna | Helgadottir, Hafdis T | Sigurdsson, Asgeir | Steinthorsdottir, Valgerdur | Lindblom, Annika | Sandler, Robert S | Keku, Temitope O | Banasik, Karina | Jørgensen, Torben | Witte, Daniel R | Hansen, Torben | Pedersen, Oluf | Jinga, Viorel | Neal, David E | Catalona, William J | Wrensch, Margaret | Wiencke, John | Jenkins, Robert B | Nagore, Eduardo | Vogel, Ulla | Kiemeney, Lambertus A | Kumar, Rajiv | Mayordomo, José I | Olafsson, Jon H | Kong, Augustine | Thorsteinsdottir, Unnur | Rafnar, Thorunn | Stefansson, Kari
Nature Genetics  2011;43(11):1098-1103.
To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10−17), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10−20). rs78378222 is in the 3′ untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3′-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10−6), glioma (OR = 2.35, P = 1.0 × 10−5) and colorectal adenoma (OR = 1.39, P = 1.6 × 10−4). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88–1.27).
doi:10.1038/ng.926
PMCID: PMC3263694  PMID: 21946351
11.  Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls 
Human Molecular Genetics  2012;21(22):4980-4995.
Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21–6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10−16), 6p21 (P = 2.3 × 10−14) and 15q25 (P = 2.2 × 10−63). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16INK4A/p14ARF/CDKN2B/p15INK4B/ANRIL; rs1333040, P = 3.0 × 10−7) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10−8). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer.
doi:10.1093/hmg/dds334
PMCID: PMC3607485  PMID: 22899653
12.  Sequence variants at CYP1A1–CYP1A2 and AHR associate with coffee consumption 
Human Molecular Genetics  2011;20(10):2071-2077.
Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), the Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4 · 10−14) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3 · 10−11). An effect of ∼0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and non-smokers.
doi:10.1093/hmg/ddr086
PMCID: PMC3080612  PMID: 21357676
13.  An analysis of single nucleotide polymorphisms of 125 DNA repair genes in the Texas genome-wide association study of lung cancer with a replication for the XRCC4 SNPs 
DNA repair  2011;10(4):398-407.
DNA repair genes are important for maintaining genomic stability and limiting carcinogenesis. We analyzed all single nucleotide polymorphisms (SNPs) of 125 DNA repair genes covered by the Illumina HumanHap300 (v1.1) BeadChips in a previously conducted genome-wide association study (GWAS) of 1,154 lung cancer cases and 1,137 controls and replicated the top-hits of XRCC4 SNPs in an independent set of 597 cases and 611 controls in Texas populations. We found that six of 20 XRCC4 SNPs were associated with a decreased risk of lung cancer with a P value of 0.01 or lower in the discovery dataset, of which the most significant SNP was rs10040363 (P for allelic test = 4.89 ×10−4). Moreover, the data in this region allowed us to impute a potentially functional SNP rs2075685 (imputed P for allelic test = 1.3 ×10−3). A luciferase reporter assay demonstrated that the rs2075685G>T change in the XRCC4 promoter increased expression of the gene. In the replication study of rs10040363, rs1478486, rs9293329, and rs2075685, however, only rs10040363 achieved a borderline association with a decreased risk of lung cancer in a dominant model (adjusted OR = 0.80, 95% CI = 0.62–1.03, P = 0.079). In the final combined analysis of both the Texas GWAS discovery and replication datasets, the strength of the association was increased for rs10040363 (adjusted OR = 0.77, 95% CI = 0.66–0.89, Pdominant = 5×10−4 and P for trend = 5×10−4) and rs1478486 (adjusted OR = 0.82, 95% CI = 0.71 −0.94, Pdominant = 6×10−3 and P for trend = 3.5×10−3). Finally, we conducted a meta-analysis of these XRCC4 SNPs with available data from published GWA studies of lung cancer with a total of 12,312 cases and 47,921 controls, in which none of these XRCC4 SNPs was associated with lung cancer risk. It appeared that rs2075685, although associated with increased expression of a reporter gene and lung cancer risk in the Texas populations, did not have an effect on lung cancer risk in other populations. This study underscores the importance of replication using published data in larger populations.
doi:10.1016/j.dnarep.2011.01.005
PMCID: PMC3062723  PMID: 21296624
XRCC4; variant; Genetic susceptibility; genome-wide association study; replication study
14.  Association of a novel functional promoter variant (rs2075533 C>T) in the apoptosis gene TNFSF8 with risk of lung cancer—a finding from Texas lung cancer genome-wide association study 
Carcinogenesis  2011;32(4):507-515.
Published genome-wide association studies (GWASs) have identified few variants in the known biological pathways involved in lung cancer etiology. To mine the possibly hidden causal single nucleotide polymorphisms (SNPs), we explored all SNPs in the extrinsic apoptosis pathway from our published GWAS dataset for 1154 lung cancer cases and 1137 cancer-free controls. In an initial association analysis of 611 tagSNPs in 41 apoptosis-related genes, we identified only 10 tagSNPs associated with lung cancer risk with a P value <10−2, including four tagSNPs in DAPK1 and three tagSNPs in TNFSF8. Unlike DAPK1 SNPs, TNFSF8 rs2181033 tagged other four predicted functional but untyped SNPs (rs776576, rs776577, rs31813148 and rs2075533) in the promoter region. Therefore, we further tested binding affinity of these four SNPs by performing the electrophoretic mobility shift assay. We found that only rs2075533T allele modified levels of nuclear proteins bound to DNA, leading to significantly decreased expression of luciferase reporter constructs by 5- to –10-fold in H1299, HeLa and HCT116 cell lines compared with the C allele. We also performed a replication study of the untyped rs2075533 in an independent Texas population but did not confirm the protective effect. We further performed a mini meta-analysis for SNPs of TNFSF8 obtained from other four published lung cancer GWASs with 12  214 cases and 47  721 controls, and we found that only rs3181366 (r2 = 0.69 with the untyped rs2075533) was associated to lung cancer risk (P = 0.008). Our findings suggest a possible role of novel TNFSF8 variants in susceptibility to lung cancer.
doi:10.1093/carcin/bgr014
PMCID: PMC3066422  PMID: 21292647
15.  Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer 
Nature Genetics  2009;41(9):991-995.
We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 × 10−10 and the allelic odds ratio was 1.15 (95% confidence interval 1.10–1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.
doi:10.1038/ng.421
PMCID: PMC3313685  PMID: 19648920
16.  Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk 
Cancer research  2011;71(4):1356-1361.
Genome-wide association studies (GWAS) have identified three genomic regions, at 15q24-25.1, 5p15.33 and 6p21.33, which associate with risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P<10−5) in a recently published meta-analysis. In a GWA dataset of 1,447 lung cancer cases and 36,256 controls in Iceland, three correlated variants on 15q15.2 (rs504417, rs11853991 and rs748404) showed a significant association with lung cancer whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31 and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain and the USA and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genome-wide significance (OR=1.15, P=1.1×10−9). Another variant at the same locus, rs12050604, showed association with lung cancer (OR=1.09, 3.6×10−6) and remained significant after adjustment for rs748404 and vice versa. rs748404 is located 140 kb centromeric of the TP53BP1 gene that has been implicated in lung cancer risk. Two fully correlated, non-synonymous coding variants in TP53BP1, rs2602141 (Q1136K) and rs560191 (E353D), showed association with lung cancer in our sample set; however, this association did not remain significant after adjustment for rs748404. Our data show that one or more lung cancer risk variants of genome-wide significance and distinct from the coding variants in TP53BP1 are located at 15q15.2.
doi:10.1158/0008-5472.CAN-10-2852
PMCID: PMC3077097  PMID: 21303977
Lung cancer; genome-wide association studies; GWAS; 15q15.2; TP53BP1
18.  CDKN2A Mutations and Melanoma Risk in the Icelandic Population 
Journal of medical genetics  2008;45(5):284-289.
Background
Germline CDKN2A mutations have been observed in 20-40% of high-risk melanoma-prone families, however little is known about their prevalence in population-based series of melanoma cases and controls.
Methods
We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry-ascertained melanoma cases and 691 population-based controls from Iceland, a country in which the incidence of melanoma has increased rapidly.
Results
We identified a novel germline variant, G89D that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head & neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma.
Conclusions
This population-based study of Icelandic melanoma cases and controls showed a frequency of disease-related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consists of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population-based estimates of CDKN2A mutation frequencies are available.
doi:10.1136/jmg.2007.055376
PMCID: PMC3236640  PMID: 18178632
melanoma; CDKN2A; G89D; pancreatic cancer; population-based
19.  Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies 
Elks, Cathy E. | Perry, John R.B. | Sulem, Patrick | Chasman, Daniel I. | Franceschini, Nora | He, Chunyan | Lunetta, Kathryn L. | Visser, Jenny A. | Byrne, Enda M. | Cousminer, Diana L. | Gudbjartsson, Daniel F. | Esko, Tõnu | Feenstra, Bjarke | Hottenga, Jouke-Jan | Koller, Daniel L. | Kutalik, Zoltán | Lin, Peng | Mangino, Massimo | Marongiu, Mara | McArdle, Patrick F. | Smith, Albert V. | Stolk, Lisette | van Wingerden, Sophie W. | Zhao, Jing Hua | Albrecht, Eva | Corre, Tanguy | Ingelsson, Erik | Hayward, Caroline | Magnusson, Patrik K.E. | Smith, Erin N. | Ulivi, Shelia | Warrington, Nicole M. | Zgaga, Lina | Alavere, Helen | Amin, Najaf | Aspelund, Thor | Bandinelli, Stefania | Barroso, Ines | Berenson, Gerald S. | Bergmann, Sven | Blackburn, Hannah | Boerwinkle, Eric | Buring, Julie E. | Busonero, Fabio | Campbell, Harry | Chanock, Stephen J. | Chen, Wei | Cornelis, Marilyn C. | Couper, David | Coviello, Andrea D. | d’Adamo, Pio | de Faire, Ulf | de Geus, Eco J.C. | Deloukas, Panos | Döring, Angela | Smith, George Davey | Easton, Douglas F. | Eiriksdottir, Gudny | Emilsson, Valur | Eriksson, Johan | Ferrucci, Luigi | Folsom, Aaron R. | Foroud, Tatiana | Garcia, Melissa | Gasparini, Paolo | Geller, Frank | Gieger, Christian | Gudnason, Vilmundur | Hall, Per | Hankinson, Susan E. | Ferreli, Liana | Heath, Andrew C. | Hernandez, Dena G. | Hofman, Albert | Hu, Frank B. | Illig, Thomas | Järvelin, Marjo-Riitta | Johnson, Andrew D. | Karasik, David | Khaw, Kay-Tee | Kiel, Douglas P. | Kilpeläinen, Tuomas O. | Kolcic, Ivana | Kraft, Peter | Launer, Lenore J. | Laven, Joop S.E. | Li, Shengxu | Liu, Jianjun | Levy, Daniel | Martin, Nicholas G. | McArdle, Wendy L. | Melbye, Mads | Mooser, Vincent | Murray, Jeffrey C. | Murray, Sarah S. | Nalls, Michael A. | Navarro, Pau | Nelis, Mari | Ness, Andrew R. | Northstone, Kate | Oostra, Ben A. | Peacock, Munro | Palmer, Lyle J. | Palotie, Aarno | Paré, Guillaume | Parker, Alex N. | Pedersen, Nancy L. | Peltonen, Leena | Pennell, Craig E. | Pharoah, Paul | Polasek, Ozren | Plump, Andrew S. | Pouta, Anneli | Porcu, Eleonora | Rafnar, Thorunn | Rice, John P. | Ring, Susan M. | Rivadeneira, Fernando | Rudan, Igor | Sala, Cinzia | Salomaa, Veikko | Sanna, Serena | Schlessinger, David | Schork, Nicholas J. | Scuteri, Angelo | Segrè, Ayellet V. | Shuldiner, Alan R. | Soranzo, Nicole | Sovio, Ulla | Srinivasan, Sathanur R. | Strachan, David P. | Tammesoo, Mar-Liis | Tikkanen, Emmi | Toniolo, Daniela | Tsui, Kim | Tryggvadottir, Laufey | Tyrer, Jonathon | Uda, Manuela | van Dam, Rob M. | van Meurs, Joyve B.J. | Vollenweider, Peter | Waeber, Gerard | Wareham, Nicholas J. | Waterworth, Dawn M. | Weedon, Michael N. | Wichmann, H. Erich | Willemsen, Gonneke | Wilson, James F. | Wright, Alan F. | Young, Lauren | Zhai, Guangju | Zhuang, Wei Vivian | Bierut, Laura J. | Boomsma, Dorret I. | Boyd, Heather A. | Crisponi, Laura | Demerath, Ellen W. | van Duijn, Cornelia M. | Econs, Michael J. | Harris, Tamara B. | Hunter, David J. | Loos, Ruth J.F. | Metspalu, Andres | Montgomery, Grant W. | Ridker, Paul M. | Spector, Tim D. | Streeten, Elizabeth A. | Stefansson, Kari | Thorsteinsdottir, Unnur | Uitterlinden, André G. | Widen, Elisabeth | Murabito, Joanne M. | Ong, Ken K. | Murray, Anna
Nature genetics  2010;42(12):1077-1085.
To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P=5.4×10−60) and 9q31.2 (P=2.2×10−33), we identified 30 novel menarche loci (all P<5×10−8) and found suggestive evidence for a further 10 loci (P<1.9×10−6). New loci included four previously associated with BMI (in/near FTO, SEC16B, TRA2B and TMEM18), three in/near other genes implicated in energy homeostasis (BSX, CRTC1, and MCHR2), and three in/near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and MAGENTA pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
doi:10.1038/ng.714
PMCID: PMC3140055  PMID: 21102462
20.  Hypothetical and factual willingness to participate in biobank research 
European Journal of Human Genetics  2010;18(11):1261-1264.
In the debate on biobank regulation, arguments often draw upon findings in surveys on public attitudes. However, surveys on willingness to participate in research may not always predict actual participation rates. We compared hypothetical willingness as estimated in 11 surveys conducted in Sweden, Iceland, United Kingdom, Ireland, United States and Singapore to factual participation rates in 12 biobank studies. Studies were matched by country and approximate time frame. Of 22 pairwise comparisons, 12 suggest that factual willingness to participate in biobank research is greater than hypothetical, six indicate the converse relationship, and four are inconclusive. Factual donors, in particular when recruited in health care or otherwise face-to-face with the researcher, are possibly motivated by factors that are less influential in a hypothetical context, such as altruism, trust, and sense of duty. The value of surveys in assessing factual willingness may thus be limited.
doi:10.1038/ejhg.2010.106
PMCID: PMC2987483  PMID: 20648060
biobanks; tissue banks; genetic databases; public attitudes; trust; public surveys
21.  A Genome-Wide Association Study Identifies Susceptibility Loci for Ovarian Cancer at 2q31 and 8q24 
Goode, Ellen L. | Chenevix-Trench, Georgia | Song, Honglin | Ramus, Susan J. | Notaridou, Maria | Lawrenson, Kate | Widschwendter, Martin | Vierkant, Robert A. | Larson, Melissa C. | Kjaer, Susanne K. | Birrer, Michael J. | Berchuck, Andrew | Schildkraut, Joellen | Tomlinson, Ian | Kiemeney, Lambertus A. | Cook, Linda S. | Gronwald, Jacek | Garcia-Closas, Montserrat | Gore, Martin E. | Campbell, Ian | Whittemore, Alice S. | Sutphen, Rebecca | Phelan, Catherine | Anton-Culver, Hoda | Pearce, Celeste Leigh | Lambrechts, Diether | Rossing, Mary Anne | Chang-Claude, Jenny | Moysich, Kirsten B. | Goodman, Marc T. | Dörk, Thilo | Nevanlinna, Heli | Ness, Roberta B. | Rafnar, Thorunn | Hogdall, Claus | Hogdall, Estrid | Fridley, Brooke L. | Cunningham, Julie M. | Sieh, Weiva | McGuire, Valerie | Godwin, Andrew K. | Cramer, Daniel W. | Hernandez, Dena | Levine, Douglas | Lu, Karen | Iversen, Edwin S. | Palmieri, Rachel T. | Houlston, Richard | van Altena, Anne M. | Aben, Katja K.H. | Massuger, Leon F.A.G. | Brooks-Wilson, Angela | Kelemen, Linda E. | Le, Nhu D. | Jakubowska, Anna | Lubinski, Jan | Medrek, Krzysztof | Stafford, Anne | Easton, Douglas F. | Tyrer, Jonathan | Bolton, Kelly L. | Harrington, Patricia | Eccles, Diana | Chen, Ann | Molina, Ashley N. | Davila, Barbara N. | Arango, Hector | Tsai, Ya-Yu | Chen, Zhihua | Risch, Harvey A. | McLaughlin, John | Narod, Steven A. | Ziogas, Argyrios | Brewster, Wendy | Gentry-Maharaj, Aleksandra | Menon, Usha | Wu, Anna H. | Stram, Daniel O. | Pike, Malcolm C. | Beesley, Jonathan | Webb, Penelope M. | Chen, Xiaoqing | Ekici, Arif B. | Thiel, Falk C. | Beckmann, Matthias W. | Yang, Hannah | Wentzensen, Nicolas | Lissowska, Jolanta | Fasching, Peter A. | Despierre, Evelyn | Amant, Frederic | Vergote, Ignace | Doherty, Jennifer | Hein, Rebecca | Wang-Gohrke, Shan | Lurie, Galina | Carney, Michael E. | Thompson, Pamela J. | Runnebaum, Ingo | Hillemanns, Peter | Dürst, Matthias | Antonenkova, Natalia | Bogdanova, Natalia | Leminen, Arto | Butzow, Ralf | Heikkinen, Tuomas | Stefansson, Kari | Sulem, Patrick | Besenbacher, Sören | Sellers, Thomas A. | Gayther, Simon A. | Pharoah, Paul D.P.
Nature genetics  2010;42(10):874-879.
Ovarian cancer (OC) accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance OC susceptibility genes, we conducted a genome-wide association study (GWAS) of 507,094 SNPs in 1,768 cases and 2,354 controls, with follow-up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (BNC2)1. Here, we report on nine additional candidate loci (p≤10-4), identified after stratifying cases by histology, genotyped in an additional 4,353 cases and 6,021 controls. Two novel susceptibility loci with p≤5×10-8 were confirmed (8q24, p=8.0×10-15 and 2q31, p=3.8×10-14); two additional loci were also identified that approached genome-wide significance (3q25, p=7.1×10-8 and 17q21, p=1.4×10-7). The associations with serous OC were generally stronger than other subtypes. Analysis of HOXD1, MYC, TiPARP, and SKAP1 at these loci, and BNC2 at 9p22, supports a functional role for these genes in OC development.
doi:10.1038/ng.668
PMCID: PMC3020231  PMID: 20852632
22.  Replication of Lung Cancer Susceptibility Loci at Chromosomes 15q25, 5p15, and 6p21: A Pooled Analysis From the International Lung Cancer Consortium 
Background
Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies.
Methods
Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case–control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided.
Results
Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, Ptrend = 2 × 10−26), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, Ptrend = 1 × 10−10) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, Ptrend = 5 × 10−8) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, Ptrend = 2 × 10−5; rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, Ptrend = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer.
Conclusions
In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.
doi:10.1093/jnci/djq178
PMCID: PMC2897877  PMID: 20548021
23.  Common variants at 19p13 are associated with susceptibility to ovarian cancer 
Bolton, Kelly L. | Tyrer, Jonathan | Song, Honglin | Ramus, Susan J. | Notaridou, Maria | Jones, Chris | Sher, Tanya | Gentry-Maharaj, Aleksandra | Wozniak, Eva | Tsai, Ya-Yu | Weidhaas, Joanne | Paik, Daniel | Van Den Berg, David J. | Stram, Daniel O. | Pearce, Celeste Leigh | Wu, Anna H. | Brewster, Wendy | Anton-Culver, Hoda | Ziogas, Argyrios | Narod, Steven A. | Levine, Douglas A. | Kaye, Stanley B. | Brown, Robert | Paul, Jim | Flanagan, James | Sieh, Weiva | McGuire, Valerie | Whittemore, Alice S. | Campbell, Ian | Gore, Martin E. | Lissowska, Jolanta | Yang, Hannah | Medrek, Krzysztof | Gronwald, Jacek | Lubinski, Jan | Jakubowska, Anna | Le, Nhu D. | Cook, Linda S. | Kelemen, Linda E. | Brook-Wilson, Angela | Massuger, Leon F.A.G. | Kiemeney, Lambertus A. | Aben, Katja K.H. | van Altena, Anne M. | Houlston, Richard | Tomlinson, Ian | Palmieri, Rachel T. | Moorman, Patricia G. | Schildkraut, Joellen | Iversen, Edwin S. | Phelan, Catherine | Vierkant, Robert A. | Cunningham, Julie M. | Goode, Ellen L. | Fridley, Brooke L. | Kruger-Kjaer, Susan | Blaeker, Jan | Hogdall, Estrid | Hogdall, Claus | Gross, Jenny | Karlan, Beth Y. | Ness, Roberta B. | Edwards, Robert P. | Odunsi, Kunle | Moyisch, Kirsten B. | Baker, Julie A. | Modugno, Francesmary | Heikkinenen, Tuomas | Butzow, Ralf | Nevanlinna, Heli | Leminen, Arto | Bogdanova, Natalia | Antonenkova, Natalia | Doerk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo | Thompson, Pamela J. | Carney, Michael E. | Goodman, Marc T. | Lurie, Galina | Wang-Gohrke, Shan | Hein, Rebecca | Chang-Claude, Jenny | Rossing, Mary Anne | Cushing-Haugen, Kara L. | Doherty, Jennifer | Chen, Chu | Rafnar, Thorunn | Besenbacher, Soren | Sulem, Patrick | Stefansson, Kari | Birrer, Michael J. | Terry, Kathryn L. | Hernandez, Dena | Cramer, Daniel W. | Vergote, Ignace | Amant, Frederic | Lambrechts, Diether | Despierre, Evelyn | Fasching, Peter A. | Beckmann, Matthias W. | Thiel, Falk C. | Ekici, Arif B. | Chen, Xiaoqing | Johnatty, Sharon E. | Webb, Penelope M. | Beesley, Jonathan | Chanock, Stephen | Garcia-Closas, Montserrat | Sellers, Tom | Easton, Douglas F. | Berchuck, Andrew | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Gayther, Simon A.
Nature genetics  2010;42(10):880-884.
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world accounting for 4 percent of deaths from cancer in women1. We performed a three-phase genome-wide association study of EOC survival in 8,951 EOC cases with available survival time data, and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P=5×10−4 and 6×10−4), but did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P=3×10−9 and 4×10−11 respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1 interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.
doi:10.1038/ng.666
PMCID: PMC3125495  PMID: 20852633
24.  A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci 
Rothman, Nathaniel | Garcia-Closas, Montserrat | Chatterjee, Nilanjan | Malats, Nuria | Wu, Xifeng | Figueroa, Jonine | Real, Francisco X | Van Den Berg, David | Matullo, Giuseppe | Baris, Dalsu | Thun, Michael | Kiemeney, Lambertus A | Vineis, Paolo | De Vivo, Immaculata | Albanes, Demetrius | Purdue, Mark P | Rafnar, Thorunn | Hildebrandt, Michelle A T | Kiltie, Anne E | Cussenot, Olivier | Golka, Klaus | Kumar, Rajiv | Taylor, Jack A | Mayordomo, Jose I | Jacobs, Kevin B | Kogevinas, Manolis | Hutchinson, Amy | Wang, Zhaoming | Fu, Yi-Ping | Prokunina-Olsson, Ludmila | Burdette, Laurie | Yeager, Meredith | Wheeler, William | Tardón, Adonina | Serra, Consol | Carrato, Alfredo | García-Closas, Reina | Lloreta, Josep | Johnson, Alison | Schwenn, Molly | Karagas, Margaret R | Schned, Alan | Andriole, Gerald | Grubb, Robert | Black, Amanda | Jacobs, Eric J | Diver, W Ryan | Gapstur, Susan M | Weinstein, Stephanie J | Virtamo, Jarmo | Cortessis, Victoria K | Gago-Dominguez, Manuela | Pike, Malcolm C | Stern, Mariana C | Yuan, Jian-Min | Hunter, David | McGrath, Monica | Dinney, Colin P | Czerniak, Bogdan | Chen, Meng | Yang, Hushan | Vermeulen, Sita H | Aben, Katja K | Witjes, J Alfred | Makkinje, Remco R | Sulem, Patrick | Besenbacher, Soren | Stefansson, Kari | Riboli, Elio | Brennan, Paul | Panico, Salvatore | Navarro, Carmen | Allen, Naomi E | Bueno-de-Mesquita, H Bas | Trichopoulos, Dimitrios | Caporaso, Neil | Landi, Maria Teresa | Canzian, Federico | Ljungberg, Borje | Tjonneland, Anne | Clavel-Chapelon, Francoise | Bishop, David T | Teo, Mark T W | Knowles, Margaret A | Guarrera, Simonetta | Polidoro, Silvia | Ricceri, Fulvio | Sacerdote, Carlotta | Allione, Alessandra | Cancel-Tassin, Geraldine | Selinski, Silvia | Hengstler, Jan G | Dietrich, Holger | Fletcher, Tony | Rudnai, Peter | Gurzau, Eugen | Koppova, Kvetoslava | Bolick, Sophia C E | Godfrey, Ashley | Xu, Zongli | Sanz-Velez, José I | García-Prats, María D | Sanchez, Manuel | Valdivia, Gabriel | Porru, Stefano | Benhamou, Simone | Hoover, Robert N | Fraumeni, Joseph F | Silverman, Debra T | Chanock, Stephen J
Nature genetics  2010;42(11):978-984.
We conducted a multi-stage, genome-wide association study (GWAS) of bladder cancer with a primary scan of 589,299 single nucleotide polymorphisms (SNPs) in 3,532 cases and 5,120 controls of European descent (5 studies) followed by a replication strategy, which included 8,381 cases and 48,275 controls (16 studies). In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1; rs1014971, (P=8×10−12) maps to a non-genic region of chromosome 22q13.1; rs8102137 (P=2×10−11) on 19q12 maps to CCNE1; and rs11892031 (P=1×10−7) maps to the UGT1A cluster on 2q37.1. We confirmed four previous GWAS associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P=4×10−11) and a tag SNP for NAT2 acetylation status (P=4×10−11), as well as demonstrated smoking interactions with both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into mechanisms of carcinogenesis.
doi:10.1038/ng.687
PMCID: PMC3049891  PMID: 20972438
25.  Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior 
Thorgeirsson, Thorgeir E. | Gudbjartsson, Daniel F. | Surakka, Ida | Vink, Jacqueline M. | Amin, Najaf | Geller, Frank | Sulem, Patrick | Rafnar, Thorunn | Esko, Tõnu | Walter, Stefan | Gieger, Christian | Rawal, Rajesh | Mangino, Massimo | Prokopenko, Inga | Mägi, Reedik | Keskitalo, Kaisu | Gudjonsdottir, Iris H. | Gretarsdottir, Solveig | Stefansson, Hreinn | Thompson, John R. | Aulchenko, Yurii S. | Nelis, Mari | Aben, Katja K. | den Heijer, Martin | Dirksen, Asger | Ashraf, Haseem | Soranzo, Nicole | Valdes, Ana M | Steves, Claire | Uitterlinden, André G | Hofman, Albert | Tönjes, Anke | Kovacs, Peter | Hottenga, Jouke Jan | Willemsen, Gonneke | Vogelzangs, Nicole | Döring, Angela | Dahmen, Norbert | Nitz, Barbara | Pergadia, Michele L. | Saez, Berta | De Diego, Veronica | Lezcano, Victoria | Garcia-Prats, Maria D. | Ripatti, Samuli | Perola, Markus | Kettunen, Johannes | Hartikainen, Anna-Liisa | Pouta, Anneli | Laitinen, Jaana | Isohanni, Matti | Huei-Yi, Shen | Allen, Maxine | Krestyaninova, Maria | Hall, Alistair S | Jones, Gregory T. | van Rij, Andre M. | Mueller, Thomas | Dieplinger, Benjamin | Haltmayer, Meinhard | Jonsson, Steinn | Matthiasson, Stefan E. | Oskarsson, Hogni | Tyrfingsson, Thorarinn | Kiemeney, Lambertus A. | Mayordomo, Jose I. | Lindholt, Jes S | Pedersen, Jesper Holst | Franklin, Wilbur A. | Wolf, Holly | Montgomery, Grant W. | Heath, Andrew C. | Martin, Nicholas G. | Madden, Pamela A.F. | Giegling, Ina | Rujescu, Dan | Järvelin, Marjo-Riitta | Salomaa, Veikko | Stumvoll, Michael | Spector, Tim D | Wichmann, H-Erich | Metspalu, Andres | Samani, Nilesh J. | Penninx, Brenda W. | Oostra, Ben A. | Boomsma, Dorret I. | Tiemeier, Henning | van Duijn, Cornelia M. | Kaprio, Jaakko | Gulcher, Jeffrey R. | McCarthy, Mark I. | Peltonen, Leena | Thorsteinsdottir, Unnur | Stefansson, Kari
Nature genetics  2010;42(5):448-453.
Smoking is a risk factor for most of the diseases leading in mortality1. We conducted genome-wide association (GWA) meta-analyses of smoking data within the ENGAGE consortium to search for common alleles associating with the number of cigarettes smoked per day (CPD) in smokers (N=31,266) and smoking initiation (N=46,481). We tested selected SNPs in a second stage (N=45,691 smokers), and assessed some in a third sample (N=9,040). Variants in three genomic regions associated with CPD (P< 5·10−8), including previously identified SNPs at 15q25 represented by rs1051730-A (0.80 CPD,P=2.4·10−69), and SNPs at 19q13 and 8p11, represented by rs4105144-C (0.39 CPD, P=2.2·10−12) and rs6474412-T (0.29 CPD,P= 1.4·10−8), respectively. Among the genes at the two novel loci, are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6), and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6) highlighted in previous studies of nicotine dependence2-3. Nominal associations with lung cancer were observed at both 8p11 (rs6474412-T,OR=1.09,P=0.04) and 19q13 (rs4105144-C,OR=1.12,P=0.0006).
doi:10.1038/ng.573
PMCID: PMC3080600  PMID: 20418888

Results 1-25 (34)