| 1. |
- Antoniou, Antonis C., et al.
(författare)
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A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:10, s. 885-892
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Tidskriftsartikel (refereegranskat)abstract
- Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P-trend = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P-trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P-trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P-trend = 1.1 x 10(-7)).
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| 2. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 3. |
- Daly, Robert J., et al.
(författare)
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A palynological study of an extinct arctic ecosystem from the Palaeocene of Northern Alaska
- 2011
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Ingår i: Review of Palaeobotany and Palynology. - : Elsevier BV. - 0034-6667. ; 166:1-2, s. 107-116
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Tidskriftsartikel (refereegranskat)abstract
- The Palaeocene arctic supported a vegetation type quite distinct from the tundra and polar desert of today. Here we demonstrate, through the palynological record, the structure of this extinct vegetation and its dynamics over this period. The Late Palaeocene coal-bearing units of the Sagwon Bluffs on Alaska's North Slope (present latitude 69 degrees N) are predominantly fine-grained, non-marine and rich in palynomorph-bearing sediments. From the analysed palynological assemblage we were able to demonstrate, using 'Detrended Correspondence Analysis' (DCA) and 'Fuzzy c-Means Cluster Analysis' (FCM), 1) a complex heterogeneous ecosystem, 2) its major successional states, and 3) its development over an extended period. The climax state of the floodplain was dominated by flood-tolerant, deciduous conifers such as Metasequoia. A more heterogeneous mid-successional assemblage is represented by angiosperm and gymnosperm co-dominance with an angiosperm dominance of Corylus, while early-successional ecological groups, dominated by ferns and bryophytes, are considered to represent riparian and post-disturbance niches. The structure of this vegetation does not remain static over the course of the stratigraphic interval represented. We observe a particularly dramatic ecological change for instance, following the deposition of a large conglomeratic unit. It is hypothesized that this corresponds to altered drainage and/or precipitation on the North Slope. The vegetation examined herein shows marked similarities to that of other palaeobotanical studies from various sites of similar age at high northern latitudes. It is hence considered to represent an extensive and long-lived circumpolar arctic biome. (C) 2011 Elsevier B.V. All rights reserved.
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| 4. |
- Gaudet, Mia M., et al.
(författare)
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Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer
- 2010
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 6:10
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Tidskriftsartikel (refereegranskat)abstract
- The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
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| 5. |
- Voight, Benjamin F, et al.
(författare)
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Plasma HDL cholesterol and risk of myocardial infarction : a mendelian randomisation study
- 2012
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 380:9841, s. 572-580
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)).INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
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| 6. |
- Assimes, Themistocles L., et al.
(författare)
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Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies
- 2010
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 56:19, s. 1552-1563
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Tidskriftsartikel (refereegranskat)abstract
- Objectives We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. Results A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of >= 2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. Conclusions The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study. (J Am Coll Cardiol 2010;56:1552-63) (C) 2010 by the American College of Cardiology Foundation
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| 7. |
- Bolton, Kelly L., et al.
(författare)
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Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer
- 2012
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Ingår i: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 307:4, s. 382-390
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Tidskriftsartikel (refereegranskat)abstract
- Context Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. Objective To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. Design, Setting, and Participants A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n=909) or BRCA2 (n=304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). Main Outcome Measure Five-year overall mortality. Results The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P<.001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P<.001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P<.001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P<.001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity=.003). Conclusion Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis. JAMA. 2012;307(4):382-390
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| 8. |
- Ellinghaus, David, et al.
(författare)
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Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
- 2013
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 145:2, s. 339-347
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
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| 9. |
- Franke, Andre, et al.
(författare)
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Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1118-1125
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Tidskriftsartikel (refereegranskat)abstract
- We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
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| 10. |
- Kirby, Andrew, et al.
(författare)
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Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:3, s. 299-303
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Tidskriftsartikel (refereegranskat)abstract
- Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (similar to 1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.
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