Author
Olivia Fletcher
Other affiliations: Imperial College London, University of London, Cancer Council Victoria ...read more
Bio: Olivia Fletcher is an academic researcher from Institute of Cancer Research. The author has contributed to research in topics: Breast cancer & Genome-wide association study. The author has an hindex of 57, co-authored 125 publications receiving 15430 citations. Previous affiliations of Olivia Fletcher include Imperial College London & University of London.
Papers published on a yearly basis
Papers
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University of Cambridge1, National Institutes of Health2, University of Southern California3, International Agency for Research on Cancer4, Academia Sinica5, Princess Anne Hospital6, St Mary's Hospital7, University of London8, The Breast Cancer Research Foundation9, Wellcome Trust Sanger Institute10, QIMR Berghofer Medical Research Institute11, Peter MacCallum Cancer Centre12, University of Copenhagen13, Curie Institute14, Nofer Institute of Occupational Medicine15, University of Helsinki16, Seoul National University17, University of Ulsan18, Harvard University19, Karolinska Institutet20, Agency for Science, Technology and Research21, Hannover Medical School22, Leiden University23, Erasmus University Rotterdam24, University of Minnesota25, University of Sheffield26, Mayo Clinic27, VU University Amsterdam28, Carlos III Health Institute29, University of Melbourne30, University of Otago31, Cancer Council New South Wales32, Cancer Council Victoria33, Bosch34, University of Tübingen35, German Cancer Research Center36, University of Eastern Finland37
TL;DR: To identify further susceptibility alleles, a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls was conducted, followed by a third stage in which 30 single nucleotide polymorphisms were tested for confirmation.
Abstract: Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2.0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P,1027). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P,0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
2,288 citations
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Bjarni J. Vilhjálmsson1, Jian Yang2, Hilary K. Finucane3, Alexander Gusev4 +391 more•Institutions (14)
TL;DR: LDpred is introduced, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel, and outperforms the approach of pruning followed by thresholding, particularly at large sample sizes.
Abstract: Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.
1,088 citations
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TL;DR: A meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, and identified 29,807 SNPs for further genotyping suggests that more than 1,000 additional loci are involved in breast cancer susceptibility.
Abstract: Breast cancer is the most common cancer among women Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC) The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)) Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility
1,048 citations
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Kyriaki Michailidou1, Kyriaki Michailidou2, Sara Lindström3, Sara Lindström4 +393 more•Institutions (127)
TL;DR: A genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry finds that heritability of Breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2–5-fold enriched relative to the genome- wide average.
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
1,014 citations
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TL;DR: C cervical screening has prevented an epidemic that would have killed about one in 65 of all British women born since 1950 and culminated in about 6000 deaths per year in this country, at a cost per life saved of about pound 36000.
764 citations
Cited by
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National Institutes of Health1, University of Chicago2, Duke University3, Harvard University4, University of Oxford5, GlaxoSmithKline6, Johns Hopkins University7, Yale University8, deCODE genetics9, Howard Hughes Medical Institute10, Princeton University11, Washington University in St. Louis12, University of California, Berkeley13, Stanford University14, University of Michigan15, Cornell University16, University of Washington17, University of Queensland18, Vanderbilt University19, North Carolina State University20, QIMR Berghofer Medical Research Institute21
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
7,797 citations
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Christina Fitzmaurice1, Christina Fitzmaurice2, Christina Fitzmaurice3, Tomi Akinyemiju4 +177 more•Institutions (102)
TL;DR: In this paper, the authors assess the burden of 29 cancer groups over time to provide a framework for policy discussion, resource allocation, and research focus, and evaluate cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) for 195 countries and territories by age and sex using the Global Burden of Disease study estimation methods.
Abstract: Importance The increasing burden due to cancer and other noncommunicable diseases poses a threat to human development, which has resulted in global political commitments reflected in the Sustainable Development Goals as well as the World Health Organization (WHO) Global Action Plan on Non-Communicable Diseases. To determine if these commitments have resulted in improved cancer control, quantitative assessments of the cancer burden are required. Objective To assess the burden for 29 cancer groups over time to provide a framework for policy discussion, resource allocation, and research focus. Evidence Review Cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) were evaluated for 195 countries and territories by age and sex using the Global Burden of Disease study estimation methods. Levels and trends were analyzed over time, as well as by the Sociodemographic Index (SDI). Changes in incident cases were categorized by changes due to epidemiological vs demographic transition. Findings In 2016, there were 17.2 million cancer cases worldwide and 8.9 million deaths. Cancer cases increased by 28% between 2006 and 2016. The smallest increase was seen in high SDI countries. Globally, population aging contributed 17%; population growth, 12%; and changes in age-specific rates, −1% to this change. The most common incident cancer globally for men was prostate cancer (1.4 million cases). The leading cause of cancer deaths and DALYs was tracheal, bronchus, and lung cancer (1.2 million deaths and 25.4 million DALYs). For women, the most common incident cancer and the leading cause of cancer deaths and DALYs was breast cancer (1.7 million incident cases, 535 000 deaths, and 14.9 million DALYs). In 2016, cancer caused 213.2 million DALYs globally for both sexes combined. Between 2006 and 2016, the average annual age-standardized incidence rates for all cancers combined increased in 130 of 195 countries or territories, and the average annual age-standardized death rates decreased within that timeframe in 143 of 195 countries or territories. Conclusions and Relevance Large disparities exist between countries in cancer incidence, deaths, and associated disability. Scaling up cancer prevention and ensuring universal access to cancer care are required for health equity and to fulfill the global commitments for noncommunicable disease and cancer control.
4,621 citations
01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
4,409 citations
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TL;DR: These interventions were more effective in people at higher risk of falling, including those with severe visual impairment, and home safety interventions appear to be more effective when delivered by an occupational therapist.
Abstract: As people get older, they may fall more often for a variety of reasons including problems with balance, poor vision, and dementia. Up to 30% may fall in a year. Although one in five falls may require medical attention, less than one in 10 results in a fracture.
This review looked at the healthcare literature to establish which fall prevention interventions are effective for older people living in the community, and included 159 randomised controlled trials with 79,193 participants.
Group and home-based exercise programmes, usually containing some balance and strength training exercises, effectively reduced falls, as did Tai Chi. Overall, exercise programmes aimed at reducing falls appear to reduce fractures.
Multifactorial interventions assess an individual's risk of falling, and then carry out treatment or arrange referrals to reduce the identified risks. Overall, current evidence shows that this type of intervention reduces the number of falls in older people living in the community but not the number of people falling during follow-up. These are complex interventions, and their effectiveness may be dependent on factors yet to be determined.
Interventions to improve home safety appear to be effective, especially in people at higher risk of falling and when carried out by occupational therapists. An anti-slip shoe device worn in icy conditions can also reduce falls.
Taking vitamin D supplements does not appear to reduce falls in most community-dwelling older people, but may do so in those who have lower vitamin D levels in the blood before treatment.
Some medications increase the risk of falling. Three trials in this review failed to reduce the number of falls by reviewing and adjusting medications. A fourth trial involving family physicians and their patients in medication review was effective in reducing falls. Gradual withdrawal of a particular type of drug for improving sleep, reducing anxiety, and treating depression (psychotropic medication) has been shown to reduce falls.
Cataract surgery reduces falls in women having the operation on the first affected eye. Insertion of a pacemaker can reduce falls in people with frequent falls associated with carotid sinus hypersensitivity, a condition which causes sudden changes in heart rate and blood pressure.
In people with disabling foot pain, the addition of footwear assessment, customised insoles, and foot and ankle exercises to regular podiatry reduced the number of falls but not the number of people falling.
The evidence relating to the provision of educational materials alone for preventing falls is inconclusive.
3,124 citations