Seminar 26 Sept: Modelling rate of decline (slope) of a biomarker as a quantitative genetic trait using mixed effects models: application to loss of renal function (GFR) in type 1 diabetes
UCL Genetics Institute Newsletter June 2014
New members of UGI
Matteo received his PhD in Bioengineering from the Politecnico di Milano University, Italy, under the joint supervision of Dr Manuela Sironi and Dr Linda Pattini. His research aimed at detecting signatures of natural selection in the human genome and correlating these findings with susceptibility to autoimmune diseases.
Matteo then worked at the Department of Integrative Biology, UC Berkeley, in Rasmus Nielsen's lab, as a postdoc. Here his studies focused on the development of statistical methods for sequencing data analysis.
He is now a Human Frontiers funded Research in Francois Balloux’s laboratory. He plans to pursue his research interests in population genomics, particularly on methods for demographic inferences of model and non-model species.
Florent studied Biology at the Ecole Normale Supérieure de Lyon (France) and then did his PhD at the Université Claude Bernard (Lyon 1) in interaction between the departments of Microbial Ecology and Biometry & Evolutionary Biology. He studied how the history of homologous recombination and horizontal gene transfer along bacterial cladogenesis have shaped bacterial genomes through adaptive and non-adaptive processes. Florent notably used phylogenetic approaches to unravel past ecological adaptation of clade ancestors of the model taxon Agrobacterium tumefaciens, a rhizospheric bacterium. Florent’s current work in the team of Francois Balloux at UGI will consist of studying the evolution of human pathogenic microbes from a population genomic perspective, with a particular focus on the role of recombination and gene transfer in shaping the genomic diversity of microbial genomes. New methods will be developed to model the processes of gene flow within microbial populations together with their demographic history. Characterization of such processes and their contribution to the emergence of new genotypes is the key to the identification of relevant selective pressures experienced by microbes, that would ultimately help us better prevent and manage epidemics.
Congratulations to the following members of staff:
- Nick Luscombe led on a grant awarded to UCLby the MRC for £8 million as part of the Medical Bioinformatics Initiative - http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60551-1/fulltext
- Nick Luscombe has also recently been awarded (together with Jernej Ule) a Senior Wellcome Trust Investigator award. Congratulations to Nick and Jernej!
- Matteo Fumagalli has been awarded the Human Frontiers fellowship.
EMBO conference update by Kaustubh Adhikari
The European Mathematical Genetics Meeting this year was organized in Cologne, Germany by Michael Nothnagel and others at the University of Cologne. It was two excellent days of discussion in methods and applications of statistical genetics aided by pleasant weather. David Balding, Doug Speed and Kaustubh Adhikari were participants from UGI. David was one of two invited speakers, giving a talk on ‘kinship, heritability and prediction’. About estimating kinship, he warned delegates about loose usage of the word identical-by-descent, as everybody is descended out of Africa if we allow our family tree to go back far enough. It was shown that the default method of estimating kinship in commonly used software such as Plink lack sophistication, and better estimators ought to be used. In his typical style which is popular among the students, he mentioned the trend where people claim themselves to be descendants of William Shakespeare, and public media fans attention to such news, but going back 500 years, Shakespeare might have genetic fragments shared with a million inhabitants of Britain, and the proportion shared with any one is probably less than one in a million. The other keynote speaker was Andreas Ziegler from the University of Lübeck, Germany, who discussed about the scope of Genetic Epidemiology, and how it has been redefined over the years to cover all the new directions the field was expanding to. He also showed some interesting cases where genetic epi methods were misused. A mention must be made of the talk by Bengt Bengtsson of Lund University, Sweden, who rather uniquely used the blackboard and made derivations on-spot of simple mathematical expressions to show how recombination protects against accumulation of harmful genetic mutations. Among other UGI speakers, Doug Speed presented his multi-BLUP method which combines signal from several variants in a gene or region for improved performance and lower dimensionality problem in regression of complex traits. Kaustubh Adhikari presented their findings in the Latin American consortium about how European, African and Native American ancestry relate to social perceptions of ancestry, noticing that physical factors such as skin colour play a huge role. There were many other interesting presentations, including one by Stephan Schiffels from the Wellcome Trust Sanger Institute which got the best trainee presentation award. His talk presented methods to infer population history from multiple genome sequences, which showed that using several individuals jointly from each population group improved accuracy of estimating population sizes and split times particularly for more recent events till a few hundred years, where single sequence based analysis work only for events older than a few thousand years. Some talks were more application based, such as comparing existing methods of kinship estimation in a French dataset comprising several cities to see if clusters corresponding to cities could be detected. The conference had many interesting poster presentations too, such as the claim that inverse normal transformations of non-normal complex phenotypes before association studies gives better or at least comparable performance to log-transformations in most cases. Overall, the fully-packed conference was a huge success, and the next year’s meeting is scheduled to be in Brest, France.
UGI MSc courses
MSc Genetics of Human Disease and MSc Pharmacogenetics and Stratified Medicine
MSc admissions are now underway and are going strong for both of our Masters. Deadlines[S1] for applications are 1st August 2014 for UK/EU students and 30th June 2014 for overseas applicants. Applications should be made on line by visiting the UCL website: http://www.ucl.ac.uk/prospective-students/graduate/degrees/programme-search
Our current students have now completed the taught part of the programme and have completed thier exams in May. After exams students will be doing their MSc research projects full time until the middle of August 2014. We were able to offer our students a wide range of research projects in the fields of Human Disease Genetics and Pharmacogenetics from researchers working in various UCL Research Institutes including UCL Genetics Institute, UCL Institute of Child Health, Centre for Neurology, Royal Free Hospital and UCL School of Pharmacy amongst others. Students have a choice of doing computer or lab-based projects. In September 2014, students from both courses will be giving short project presentations. All project supervisors and teaching staff are welcome to attend. The schedule of individual project presentations will be announced in August.
We are always happy to hear from our former students and this time we got a wonderful message from Tingzhu Bai who completed the MSc Pharmacogenetics and Stratified Medicine last year and will be graduating in August 2014. Tingzhu has accepted recently a job as a Safety Data Specialist at Merck & Co Global Pharmacovigilance Team. Well done Tingzhu and we wish you all the best in your new job!
MSc Computational and Genomic Medicine
The start of the new MSc programme in Computational and Genomic Medicine is postponed until September 2015. Please visit the UGI website for further information
Bloomsbury Centre for Genetics Epidemiology and Statistics (BCGES)
The Centre will run two short courses in September 2014.
Course 1: Introduction to Genetic Epidemiology in the GWAS era
(2 – 5 September 2014)
Genetic epidemiology holds great potential for personalised medicine and improved biological knowledge of disease processes. This course provides an introduction to the design, analysis and interpretation of genetic studies of disease, with a focus on state of the art analysis of genomewide association scans. Throughout the course participants will gain practical experience of analysing genetic data in population and family studies. By the end of the course participants will have an understanding of the fundamental concepts of genetic epidemiology, will have a working knowledge of the terminology and current status of the field, and will be able to perform many basic analyses of genetic data.
Course 2: High throughput sequencing in disease studies
(8 – 12 September 2014)
Rapidly developing technologies now allow genomes to be sequenced more quickly and cheaply than ever before. This course will cover state of the art methods and applications of next generation sequencing. The course runs over 4 days and participants will be introduced to tools for analysing high throughput sequence data, including methods for measuring copy number variants and allele-specific expression, and conducting disease association analysis with sequence data. There will be considerable opportunities to gain practical experience with new data types such as whole genome sequence, RNA- and ChIP-seq data. By the end of the course participants will have a broad knowledge of the state of the art and will be well equipped to analyse their own data.
For further information and to book your place visit our website.
Tuesday 3 June 2014, 1-2pm (Manson, LSHTM) - Dr Sandra Beleza, Lecturer in Genetics, University of Leicester
Tuesday 6th June – Fisher Centre for Computational Biology
R.A.Fisher and a century of statistical estimation in human genetics
Tuesday 1 July - Beer & Pizza evening on Psychiatric Genetics. This event is free but registration is required via Eventbrite
Tuesday 8 July (Kennedy LT, Institute of Child Health) - BCGES annual meeting in conjunction with SEGEG. This event is free but registration is required via Eventbrite
Other News & Publications
Haworth, C.M.A., & Davis, O.S.P. (2014). From observational to dynamic genetics. Front. Genet. 5:6. http://dx.doi.org/10.3389/fgene.2014.00006
"Twin and family studies have shown that most traits are at least moderately heritable. But what are the implications of finding genetic influence for the design of intervention and prevention programs? For complex traits, heritability does not mean immutability, and research has shown that genetic influences can change with age, context and in response to behavioural and drug interventions. The most significant implications for intervention will come when we move from observational genetics to investigating dynamic genetics, including genetically sensitive interventions. Future interventions should be designed to overcome genetic risk and draw upon genetic strengths by changing the environment.”
A Genome-Wide Association Study Identifies Variants in Casein Kinase II (CSNK2A2) to be Associated with Leukocyte Telomere Length in a Punjabi Sikh Diabetic Cohort. Saxena R, Bjonnes A, Prescott J, Dib P, Natt P, Lane J, Lerner M, Cooper JA, Ye Y, Li KW, Maubaret CG, Codd V, Brackett D, Mirabello L, Kraft P, Dinney CP, Stowell D, Peyton M, Ralhan S, Wander GS, Mehra NK, Salpea KD, Gu J, Wu X, Mangino M, Hunter DJ, De Vivo I, Humphries SE, Samani NJ, Spector TD, Savage SA, Sanghera DK.Circ Cardiovasc Genet. 2014 May 3. [Epub ahead of print]
Uses the different LD patterns in different ethnic groups to identify a novel GWAS hit for telomere length in Punjabi Sikhs. The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in Caucasians due to significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates TRF1 and plays an important role for regulation of telomere length homoeostasis.
Association between short leukocyte telomere length, endotoxemia, and severe periodontitis in people with diabetes: a cross-sectional survey.Masi S, Gkranias N, Li K, Salpea KD, Parkar M, Orlandi M, Suvan JE, Eng HL, Taddei S, Patel K, Darbar U, Donos N, Deanfield JE, Hurel S, Humphries SE, D'Aiuto F.Diabetes Care. 2014 Apr;37(4):1140-7. doi: 10.2337/dc13-2106.
A collaboration with colleagues in the Eastman Dental School. Shortened leukocyte telomere length (LTL) and diagnosis of periodontitis are associated with an increased risk of complications and mortality in diabetes. We show that short LTL is associated with endotoxemia and diagnosis of periodontitis in people with diabetes. LTL shortening might represent a novel biological pathway accounting for previous epidemiological data that documented higher prevalence of diabetes and its complications in people with periodontitis and vice versa.
Novel Genetic Approach to Investigate the Role of Plasma Secretory Phospholipase A2 (sPLA2)-V Isoenzyme in Coronary Heart Disease: Modified Mendelian Randomization Analysis Using PLA2G5 Expression Levels. Holmes MV, Exeter HJ, Folkersen L, Nelson CP, Guardiola M, Cooper JA, Sofat R, Boekholdt SM, Khaw KT, Li KW, Smith AJ, Van't Hooft F, Eriksson P, Franco-Cereceda A, Asselbergs FW, Boer JM, Onland-Moret NC, Hofker M, Erdmann J, Kivimaki M, Kumari M, Reiner AP, Keating BJ, Humphries SE, Hingorani AD, Mallat Z, Samani NJ, Talmud PJ; CARDIoGRAM Consortium*.Circ Cardiovasc Genet. 2014 Apr 1;7(2):144-50. doi: 10.1161/CIRCGENETICS.113.000271. Epub 2014 Feb 21.
Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis. We identified the SNPin PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA2-V levels, and tested the association of this SNP with sPLA2 activity and CHD events in 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression (P=5.1×10(-6)), but no association of rs525380C>A with plasma sPLA2. In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P=0.20). The evidence does not support a causal role for sPLA2-V in CHD.
Mendelian randomization of blood lipids for coronary heart disease.Holmes MV, Asselbergs FW, Palmer TM, Drenos F, Lanktree MB, Nelson CP, Dale CE, Padmanabhan S, Finan C, Swerdlow DI, Tragante V, van Iperen EP, Sivapalaratnam S, Shah S, Elbers CC, Shah T, Engmann J, Giambartolomei C, White J, Zabaneh D, Sofat R, McLachlan S; on behalf of the UCLEB consortium, Doevendans PA, Balmforth AJ, Hall AS, North KE, Almoguera B, Hoogeveen RC, Cushman M, Fornage M, Patel SR, Redline S, Siscovick DS, Tsai MY, Karczewski KJ, Hofker MH, Verschuren WM, Bots ML, van der Schouw YT, Melander O, Dominiczak AF, Morris R, Ben-Shlomo Y, Price J, Kumari M, Baumert J, Peters A, Thorand B, Koenig W, Gaunt TR, Humphries SE, Clarke R, Watkins H, Farrall M, Wilson JG, Rich SS, de Bakker PI, Lange LA, Davey Smith G, Reiner AP, Talmud PJ, Kivimäki M, Lawlor DA, Dudbridge F, Samani NJ, Keating BJ, Hingorani AD, Casas JP.Eur Heart J. 2014 Jan 27. [Epub ahead of print]
Uses Mendelian Randomisation approaches and multi gene SNP score in 62,199 participants and 12,099 CHD events, to confirm the causal association between elevated LDL-C and CHD and refute the association between low HDL and CHD as being causal
Hellenthal, G.; Busby, G.B.; Band, G.; Wilson, J.F.; Capelli, C.; Falush, D.; and Myers S. (2014) A genetic atlas of human admixture history, Science 343:747-51.
The study used genome-wide DNA from 95 world-wide populations to create an interactive genetic atlas (available at www.admixturemap.paintmychromosomes.com) detailing which world-wide groups have intermixed -- and when -- over the past 4,500 years. This map identifies genetic contributions likely reflecting the Mongol Empire of Genghis Khan, different routes of the Arab Slave Trade, the migration of Slavic-speaking peoples across East Europe, European colonization of the Americas, Silk Road traders, and descendants of Alexander the Great's army in a geographically isolated group from Pakistan, among others.
Mark Thomas & David Balding - http://www.ucl.ac.uk/mace-lab/genetic-ancestry
Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics. Giambartolomei C, Vukcevic D, Schadt EE, Franke L, Hingorani AD, Wallace C, Plagnol V.
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