• 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; et al. (Nature Pub. Co., 2008-03-01)
      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 x 10(-13) and 7.7 x 10(-9), respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.
    • 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; et al. (Nature Publishing Group, 2011-11)
      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).
    • A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer.

      Gudmundsson, Julius; Sulem, Patrick; Gudbjartsson, Daniel F; Masson, Gisli; Agnarsson, Bjarni A; Benediktsdottir, Kristrun R; Sigurdsson, Asgeir; Magnusson, Olafur Th; Gudjonsson, Sigurjon A; Magnusdottir, Droplaug N; et al. (2012-12)
      In 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. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 × 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.
    • Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes

      Gudmundsson, Julius; Sulem, Patrick; Steinthorsdottir, Valgerdur; Bergthorsson, Jon T; Thorleifsson, Gudmar; Manolescu, Andrei; Rafnar, Thorunn; Gudbjartsson, Daniel; Agnarsson, Bjarni A; Baker, Adam; et al. (Nature Pub. Co., 2007-08-01)
      We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.