| 1. |
- Gatchell, Michael, et al.
(författare)
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Commissioning of the DESIREE storage rings - a new facility for cold ion-ion collisions
- 2014
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Ingår i: XXVIII International Conference on Photonic, Electronic and Atomic Collisions (ICPEAC 2013). - : Institute of Physics (IOP). ; 488:1
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Konferensbidrag (refereegranskat)abstract
- We report on the ongoing commissioning of the Double ElectroStatic Ion Ring ExpEriment, DESIREE, at Stockholm University. Beams of atomic carbon anions (C-) and smaller carbon anion molecules (C-2(-), C-3(-), C-4(-) etc.) have been produced in a sputter ion source, accelerated to 10 keV or 20 keV, and stored successfully in the two electrostatic rings. The rings are enclosed in a common vacuum chamber cooled to below 13 Kelvin. The DESIREE facility allows for studies of internally relaxed single isolated atomic, molecular and cluster ions and for collision experiments between cat-and anions down to very low center-of-mass collision energies (meV scale). The total thermal load of the vacuum chamber at this temperature is measured to be 32 W. The decay rates of stored ion beams have two components: a non-exponential component caused by the space charge of the beam itself which dominates at early times and an exponential term from the neutralization of the beam in collisions with residual gas at later times. The residual gas limited storage lifetime of carbon anions in the symmetric ring is over seven minutes while the 1/e lifetime in the asymmetric ring is measured to be about 30 seconds. Although we aim to improve the storage in the second ring, the number of stored ions are now sufficient for many merged beams experiments with positive and negative ions requiring milliseconds to seconds ion storage.
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| 2. |
- Hartman, Henrik, et al.
(författare)
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First storage of ion beams in the Double Electrostatic Ion-Ring Experiment : DESIREE
- 2013
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Ingår i: Review of Scientific Instruments. - : American Institute of Physics (AIP). - 0034-6748 .- 1089-7623. ; 84:5
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Tidskriftsartikel (refereegranskat)abstract
- We report on the first storage of ion beams in the Double ElectroStatic Ion Ring ExpEriment, DESIREE, at Stockholm University. We have produced beams of atomic carbon anions and small carbon anion molecules (Cn-, n = 1, 2, 3, 4) in a sputter ion source. The ion beams were accelerated to 10 keV kinetic energy and stored in an electrostatic ion storage ring enclosed in a vacuum chamber at 13 K. For 10 keV C2- molecular anions we measure the residual-gas limited beam storage lifetime to be 448 s +/- 18 s with two independent detector systems. Using the measured storage lifetimes we estimate that the residual gas pressure is in the 10-14 mbar range. When high current ion beams are injected, the number of stored particles does not follow a single exponential decay law as would be expected for stored particles lost solely due to electron detachment in collision with the residual-gas. Instead, we observe a faster initial decay rate, which we ascribe to the effect of the space charge of the ion beam on the storage capacity.
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| 3. |
- Ho, Peh Joo, et al.
(författare)
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Comparison of self-reported and register-based hospital medical data on comorbidities in women
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer patients commonly present with comorbidities which are known to influence treatment decisions and survival. We aim to examine agreement between self-reported and register-based medical records (National Patient Register [NPR]). Ascertainment of nine conditions, using individually-linked data from 64,961 women enrolled in the Swedish KARolinska MAmmography Project for Risk Prediction of Breast Cancer (KARMA) study. Agreement was assessed using observed proportion of agreement (overall agreement), expected proportion of agreement, and Cohen's Kappa statistic. Two-stage logistic regression models taking into account chance agreement were used to identify potential predictors of overall agreement. High levels of overall agreement (i.e. ≥86.6%) were observed for all conditions. Substantial agreement (Cohen's Kappa) was observed for myocardial infarction (0.74), diabetes (0.71) and stroke (0.64) between self-reported and NPR data. Moderate agreement was observed for preeclampsia (0.51) and hypertension (0.46). Fair agreement was observed for heart failure (0.40) and polycystic ovaries or ovarian cysts (0.27). For hyperlipidemia (0.14) and angina (0.10), slight agreement was observed. In most subgroups we observed negative specific agreement of >90%. There is no clear reference data source for ascertainment of conditions. Negative specific agreement between NPR and self-reported data is consistently high across all conditions.
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| 4. |
- Thomas, Richard D., et al.
(författare)
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DESIREE : Physics with cold stored ion beams
- 2015
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Ingår i: DR2013. - : EDP Sciences. ; 84, s. 01004-01004
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Konferensbidrag (refereegranskat)abstract
- Here we will briefly describe the commissioning of the Double ElectroStatic Ion Ring ExpEriment (DESIREE) facility at Stockholm University, Sweden. This device uses purely electrostatic focussing and deflection elements and allows ion beams of opposite charge to be confined under extreme high vacuum and cryogenic conditions in separate rings and then merged over a common straight section. This apparatus allows for studies of interactions between cations and anions at very low and well-defined centre-of-mass energies (down to a few meV) and at very low internal temperatures (down to a few K).
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| 5. |
- Hartman, Mikael
(författare)
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Risk and prognosis of breast cancer among women at high risk of the disease
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall objectives of this thesis were to increase our understanding of the risk and prognosis of breast cancer using the high risk groups of women with bilateral and familial breast cancer. Data from the Swedish Cancer Register, the Multi-Generation Register and the Cause of Death register was used in Paper I-III to identify women with bilateral cancer and study risk and prognosis of the disease. The incidence of synchronous breast cancer (< 3 months of first cancer) increased by age and by 40% during the 1970s, whilst the incidence of metachronous cancer (≥ 3months of first cancer) decreased by age and by about 30% since the early 1980s most likely due to increasing use of adjuvant therapy. In the first 20 years following a diagnosis of primary breast cancer, the incidence of metachronous cancer decreased from about 0.8% to 0.4%/yr in patients diagnosed with the first breast cancer before age 45 years, whilst the incidence remained stable at 0.5-0.6%/yr among those who were older than 45 years at diagnosis. After 30 years of follow-up, the cumulative risk of metachronous bilateral breast cancer approached 15% regardless of age at first primary breast cancer. Women who developed bilateral cancer within 5 years and before age 50 were 3.9 times (95% CI 3.5-4.5) more likely to die from breast cancer than women with unilateral cancer. Women with a bilateral cancer diagnosed more than 10 years after the first cancer had a prognosis similar to that of a unilateral breast cancer. Adjuvant chemotherapy of primary cancer is a predictor of poor survival after diagnosis of early metachronous cancers. In paper III we compared the incidence patterns of familial and non-familial bilateral disease to the risk of breast cancer in twin sisters identified using the Twin Registers of Sweden, Finland and Denmark. We observed differences in risk of breast cancer that are up to 5 to 7-fold larger in absolute terms with an entirely different age pattern when comparing the risk of disease in the opposite breast and in twin sisters to the general female population. The risk of cancer in the non-affected twin and the opposite breast was not affected by age or time since first event. The relative risk of familial bilateral cancer was 52% higher (IRR 1.52, 95%CI; 1.42-1.63) and the relative risk in the dizygotic twin sister was 26% lower (IRR 0.74 95%CI; 0.61-0.90) compared to the risk of non-familial bilateral cancer. In paper IV we assessed if breast cancer prognosis is inherited using a linked data set from the Swedish Cancer Register and the Multi-Generation register. We identified 3,618 mother-daughter and sister pairs with breast cancer and classified 5-year breast cancer specific prognosis among proband (mother or oldest sister) into tertiles as poor, intermediary or good. After adjusting for potential confounders daughters and sisters of a proband with poor prognosis had a 60 percent higher 5-year breast cancer mortality compared a proband with good prognosis (relative risk 1.6; 95%CI 1.2-2.2; p for trend 0.002). In conclusion, the risk of familial disease is high and differs by age from the risk in the general population. The risk of bilateral breast cancer is high and prognosis is poor and both related to adjuvant therapy. Finally there is evidence that breast cancer prognosis is inherited.
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| 6. |
- Johansson, Henrik J., et al.
(författare)
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Breast cancer quantitative proteome and proteogenomic landscape
- 2019
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.
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| 7. |
- Kar, Siddhartha P., et al.
(författare)
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The association between weight at birth and breast cancer risk revisited using Mendelian randomisation
- 2019
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 34:6, s. 591-600
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Tidskriftsartikel (refereegranskat)abstract
- Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10 −8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval 0.73–1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, genetically-predicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study.
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| 8. |
- Kaufmann, Tobias, et al.
(författare)
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Common brain disorders are associated with heritable patterns of apparent aging of the brain
- 2019
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Ingår i: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 22:10, s. 1617-
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Tidskriftsartikel (refereegranskat)abstract
- Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.
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| 9. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 10. |
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| 11. |
- Lytsy, Per, 1968-, et al.
(författare)
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Misinterpretations of P-values and statistical tests persist among researchers and professionals working with statistics and epidemiology
- 2022
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Ingår i: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 127:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim was to investigate inferences of statistically significant test results among persons with more or less statistical education and research experience.Methods: A total of 75 doctoral students and 64 statisticians/epidemiologist responded to a web questionnaire about inferences of statistically significant findings. Participants were asked about their education and research experience, and also whether a 'statistically significant' test result (P = 0.024, alpha-level 0.05) could be inferred as proof or probability statements about the truth or falsehood of the null hypothesis (H-0) and the alternative hypothesis (H-1).Results: Almost all participants reported having a university degree, and among statisticians/epidemiologist, most reported having a university degree in statistics and were working professionally with statistics. Overall, 9.4% of statisticians/epidemiologist and 24.0% of doctoral students responded that the statistically significant finding proved that H-0 is not true, and 73.4% of statisticians/epidemiologists and 53.3% of doctoral students responded that the statistically significant finding indicated that H(0 )is improbable. Corresponding numbers about inferences about the alternative hypothesis (H-1) were 12.0% and 6.2% about proving H-1 being true and 62.7 and 62.5% for the conclusion that H-1 is probable. Correct inferences to both questions, which is that a statistically significant finding cannot be inferred as either proof or a measure of a hypothesis' probability, were given by 10.7% of doctoral students and 12.5% of statisticians/epidemiologists.Conclusions: Misinterpretation of P-values and statistically significant test results persists also among persons who have substantial statistical education and who work professionally with statistics.
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| 12. |
- Mueller, Stefanie H., et al.
(författare)
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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- 2023
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Ingår i: Genome Medicine. - : BioMed Central (BMC). - 1756-994X .- 1756-994X. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.
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| 13. |
- Ning, Yilin, et al.
(författare)
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Handling ties in continuous outcomes for confounder adjustment with rank-ordered logit and its application to ordinal outcomes
- 2020
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Ingår i: Statistical Methods in Medical Research. - : SAGE Publications. - 0962-2802 .- 1477-0334. ; 29:2, s. 437-454
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Tidskriftsartikel (refereegranskat)abstract
- The rank-ordered logit (rologit) model was recently introduced as a robust approach for analysing continuous outcomes, with the linear exposure effect estimated by scaling the rank-based log-odds estimate. Here we extend the application of the rologit model to continuous outcomes with ties and ordinal outcomes treated as imperfectly-observed continuous outcomes. By identifying the functional relationship between survival times and continuous outcomes, we explicitly establish the equivalence between the rologit and Cox models to justify the use of the Breslow, Efron and perturbation methods in the analysis of continuous outcomes with ties. Using simulation, we found all three methods perform well with few ties. Although an increasing extent of ties increased the bias of the log-odds and linear effect estimates and resulted in reduced power, which was somewhat worse when the model was mis-specified, the perturbation method maintained a type I error around 5%, while the Efron method became conservative with heavy ties but outperformed Breslow. In general, the perturbation method had the highest power, followed by the Efron and then the Breslow method. We applied our approach to three real-life datasets, demonstrating a seamless analytical workflow that uses stratification for confounder adjustment in studies of continuous and ordinal outcomes.
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| 14. |
- Sandberg, Maria E. C., et al.
(författare)
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Influence of radiotherapy for the first tumor on aggressiveness of contralateral breast cancer
- 2013
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 132:10, s. 2388-2394
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to investigate if characteristics of contralateral breast cancer (CBC) are influenced by adjuvant radiotherapy for the first breast cancer. Using information from population-based registers and medical records, we analyzed two cohorts comprising all women with CBC diagnosed >3 months after their first cancer (809 patients in Stockholm 19762005 and 750 patients in South Sweden 19772005). We used Poisson regression to calculate risk of distant metastasis after CBC, comparing patients treated and not treated with radiotherapy for the first cancer. Logistic regression was used to estimate odds ratio (OR) of more aggressive tumor characteristics in the second cancer, compared to the first. For patients with CBC in Stockholm with <5 years between the cancers radiotherapy for the first cancer conferred a nearly doubled risk of distant metastasis [incidence rate ratio (IRR) = 1.91; 95% confidence interval (CI): 1.272.88], compared to those not treated with radiotherapy. This was replicated in the South Swedish cohort [IRR = 2.12 (95% CI: 1.403.23)]. In Stockholm, we found an increased odds that, following radiotherapy, a second cancer was of more advanced TNM-stage [OR 2.16 (95% CI 1.134.11)] and higher histological grade [OR = 2.00 (95% CI 1.083.72)] compared to the first, for patients with CBC with <5 years between the cancers. No effect on any of the investigated outcomes was seen for patients diagnosed with CBC >5 years from the first cancer. In conclusion, patients diagnosed with CBC within 5 years had worse prognosis and more aggressive tumor characteristics of the second cancer, if they had received radiotherapy for their first cancer, compared to no radiotherapy.
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| 15. |
- Sjöberg, Mikael, 1969-
(författare)
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Wrestling with Textual Violence : A Case Study of the Jephthah Narrative in Antiquity and Modernity with Special Regard to Gender
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- How may readers handle the encounter with violence in a “classical text”? The purpose of this thesis is to contribute to the debate on the ethics of biblical interpretation with special regard to feminism. To fulfil that aim, a case study of the narrative of Jephthah is made and its implications are discussed at a more general level. Featuring a judge, who sacrifices his virginal daughter to the deity, this narrative raises crucial issues of ethics and gender. The case study consists of a comparative analysis of six different versions of the Jephthah narrative: the biblical text of Judges 10:6–12:7, two Jewish 1st century rewritings thereof (Pseudo-Philo’s Liber Antiquitatum Biblicarum 39–40 and Josephus’ Jewish Antiquities 5.255–5.270), a musical oratorio of the late Baroque period (Handel’s Jephtha, 1751) and two examples of 20th century fiction (E. L. Grant Watson’s novel A Mighty Man of Valour, 1939, and Amos Oz’ short story “Upon This Evil Earth” from the collection Where the Jackals Howl, 1981). Using narratology as the methodological tool for comparison, five main interpretative strategies are detected and synthesised: condemnation, identification, glorification, alienation and censure. These strategies are then assessed according to their consequences for the reader’s understanding of the power relations in the narrative and according to how they serve the reader as an impetus for change. They are also used as a point of departure for a critical discussion of Elisabeth Schüssler Fiorenza’s and Daniel Patte’s programmes for an ethics of biblical interpretation. Finally, an argument is brought forward in favour of interpretative pluralism and of the notion that biblical studies should stand in the service of the general public.
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| 16. |
- Thompson, Paul M., et al.
(författare)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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Ingår i: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Tidskriftsartikel (refereegranskat)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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| 17. |
- Uggla, Maria, et al.
(författare)
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Future Swedish 3D City Models : Specifications, Test Data, and Evaluation
- 2023
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Ingår i: ISPRS International Journal of Geo-Information. - : MDPI AG. - 2220-9964. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Three-dimensional city models are increasingly being used for analyses and simulations. To enable such applications, it is necessary to standardise semantically richer city models and, in some cases, to connect the models with external data sources. In this study, we describe the development of a new Swedish specification for 3D city models, denoted as 3CIM, which is a joint effort between the three largest cities in Sweden—Stockholm, Gothenburg, and Malmö. Technically, 3CIM is an extension of the OGC standard CityGML 2.0, implemented as an application domain extension (ADE). The ADE is semantically thin, mainly extending CityGML 2.0 to harmonise with national standards; in contrast, 3CIM is mainly based on linkages to external databases, registers, and operational systems for the semantic part. The current version, 3CIM 1.0, includes various themes, including Bridge, Building, Utility, City Furniture, Transportation, Tunnel, Vegetation, and Water. Three test areas were created with 3CIM data, one in each city. These data were evaluated in several use-cases, including visualisation as well as daylight, noise, and flooding simulations. The conclusion from these use-cases is that the 3CIM data, together with the linked external data sources, allow for the inclusion of the necessary information for the visualisation and simulations, but extract, transform, and load (ETL) processes are required to tailor the input data. The next step is to implement 3CIM within the three cities, which will entail several challenges, as discussed at the end of the paper.
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| 18. |
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| 19. |
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| 20. |
- Zeng, Chenjie, et al.
(författare)
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
- 2016
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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