Browsing by Author "Hveem, Kristian"
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Sanna, S; Li, BS; Mulas, A; Sidore, C; Kang, HM; Jackson, AU; Piras, MG; Usala, G; Maninchedda, G; Sassu, A; Serra, F; Palmas, MA; Wood, WH; Njølstad, Inger; Laakso, M; Hveem, Kristian; Tuomilehto, J; Lakka, TA; Rauramaa, R; Boehnke, M; Cucca, F; Uda, M; Schlessinger, D; Nagaraja, R; Abecasis, GR (Journal article; Tidsskriftartikkel; Peer reviewed, 2011)[+][-]
Abstract: Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ~10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci. URI: http://hdl.handle.net/10037/4016 File(s) in this item: 1
article.pdf (540.7Kb) -
Parikh, H; Wang, ZM; Pettigrew, KA; Jia, JP; Daugherty, S; Yeager, M; Jacobs, KB; Hutchinson, A; Burdett, L; Cullen, M; Qi, LQ; Boland, J; Collins, I; Albert, TJ; Vatten, Lars Johan; Hveem, Kristian; Njølstad, Inger; Cancel-Tassin, G; Cussenot, O; Valeri, A; Virtamo, J; Thun, MJ; Feigelson, HS; Diver, WR; Chatterjee, N; Thomas, G; Albanes, D; Chanock, SJ; Hunter, DJ; Hoover, R; Hayes, RB; Berndt, SI; Sampson, J; Amundadottir, L (Journal article; Tidsskriftartikkel; Peer reviewed, 2011)[+][-]
Abstract: Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56 kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case–control studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P = 0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P = 3.41 × 10−4, per-allele trend odds ratio (OR) = 0.77, 95% CI = 0.67–0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage 8 or stage ≥III (P = 0.31, per-allele trend OR = 1.12, 95% CI = 0.90–1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61 ng/ml, 95% CI = 1.49–1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12 ng/ml, 95% CI = 0.96–1.28) (P = 9.70 × 10−5). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy. URI: http://hdl.handle.net/10037/4015 File(s) in this item: 1
article.pdf (332.2Kb)
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