Dataset Information

13K T2D-GENES analysis files

ABSTRACT: This data set includes the following summary level data files used for the 13k analysis of T2D-GENES data: wes.variants.list: list of variants to keep for any analysis of the exomes data wes.assoc.samples.list: list of samples to keep for association analysis wes.assoc.variants.list: list of variants to keep for association analysis wes.sv.assoc.txt: single variant association analysis results wes.gene.ptv.variants.list.txt: list of protein truncating variants to use in gene-level analysis wes.gene.ptv.assoc.txt: results from gene-level tests of protein truncating variants wes.gene.nsstrict.variants.list.txt: list of NSstrict variants to use in gene-level analysis wes.gene.nsstrict.assoc.txt: results from gene-level tests of NSstrict variants wes.gene.nsbroad.variants.list.txt: list of NSbroad variants to use in gene-level analysis wes.gene.nsbroad.assoc.txt: results from gene-level tests of NSbroad variants wes.gene.ns.variants.list.txt: list of non synonymous variants to use in gene-level analysis wes.gene.ns.assoc.txt: results from gene-level tests of non synonymous variants

PROVIDER: EGAD00010001188 | EGA |

REPOSITORIES: EGA

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Publications

The genetic architecture of type 2 diabetes.

Fuchsberger Christian C Flannick Jason J Teslovich Tanya M TM Mahajan Anubha A Agarwala Vineeta V Gaulton Kyle J KJ Ma Clement C Fontanillas Pierre P Moutsianas Loukas L McCarthy Davis J DJ Rivas Manuel A MA Perry John R B JRB Sim Xueling X Blackwell Thomas W TW Robertson Neil R NR Rayner N William NW Cingolani Pablo P Locke Adam E AE Tajes Juan Fernandez JF Highland Heather M HM Dupuis Josee J Chines Peter S PS Lindgren Cecilia M CM Hartl Christopher C Jackson Anne U AU Chen Han H Huyghe Jeroen R JR van de Bunt Martijn M Pearson Richard D RD Kumar Ashish A Müller-Nurasyid Martina M Grarup Niels N Stringham Heather M HM Gamazon Eric R ER Lee Jaehoon J Chen Yuhui Y Scott Robert A RA Below Jennifer E JE Chen Peng P Huang Jinyan J Go Min Jin MJ Stitzel Michael L ML Pasko Dorota D Parker Stephen C J SCJ Varga Tibor V TV Green Todd T Beer Nicola L NL Day-Williams Aaron G AG Ferreira Teresa T Fingerlin Tasha T Horikoshi Momoko M Hu Cheng C Huh Iksoo I Ikram Mohammad Kamran MK Kim Bong-Jo BJ Kim Yongkang Y Kim Young Jin YJ Kwon Min-Seok MS Lee Juyoung J Lee Selyeong S Lin Keng-Han KH Maxwell Taylor J TJ Nagai Yoshihiko Y Wang Xu X Welch Ryan P RP Yoon Joon J Zhang Weihua W Barzilai Nir N Voight Benjamin F BF Han Bok-Ghee BG Jenkinson Christopher P CP Kuulasmaa Teemu T Kuusisto Johanna J Manning Alisa A Ng Maggie C Y MCY Palmer Nicholette D ND Balkau Beverley B Stančáková Alena A Abboud Hanna E HE Boeing Heiner H Giedraitis Vilmantas V Prabhakaran Dorairaj D Gottesman Omri O Scott James J Carey Jason J Kwan Phoenix P Grant George G Smith Joshua D JD Neale Benjamin M BM Purcell Shaun S Butterworth Adam S AS Howson Joanna M M JMM Lee Heung Man HM Lu Yingchang Y Kwak Soo-Heon SH Zhao Wei W Danesh John J Lam Vincent K L VKL Park Kyong Soo KS Saleheen Danish D So Wing Yee WY Tam Claudia H T CHT Afzal Uzma U Aguilar David D Arya Rector R Aung Tin T Chan Edmund E Navarro Carmen C Cheng Ching-Yu CY Palli Domenico D Correa Adolfo A Curran Joanne E JE Rybin Denis D Farook Vidya S VS Fowler Sharon P SP Freedman Barry I BI Griswold Michael M Hale Daniel Esten DE Hicks Pamela J PJ Khor Chiea-Chuen CC Kumar Satish S Lehne Benjamin B Thuillier Dorothée D Lim Wei Yen WY Liu Jianjun J van der Schouw Yvonne T YT Loh Marie M Musani Solomon K SK Puppala Sobha S Scott William R WR Yengo Loïc L Tan Sian-Tsung ST Taylor Herman A HA Thameem Farook F Wilson Gregory G Wong Tien Yin TY Njølstad Pål Rasmus PR Levy Jonathan C JC Mangino Massimo M Bonnycastle Lori L LL Schwarzmayr Thomas T Fadista João J Surdulescu Gabriela L GL Herder Christian C Groves Christopher J CJ Wieland Thomas T Bork-Jensen Jette J Brandslund Ivan I Christensen Cramer C Koistinen Heikki A HA Doney Alex S F ASF Kinnunen Leena L Esko Tõnu T Farmer Andrew J AJ Hakaste Liisa L Hodgkiss Dylan D Kravic Jasmina J Lyssenko Valeriya V Hollensted Mette M Jørgensen Marit E ME Jørgensen Torben T Ladenvall Claes C Justesen Johanne Marie JM Käräjämäki Annemari A Kriebel Jennifer J Rathmann Wolfgang W Lannfelt Lars L Lauritzen Torsten T Narisu Narisu N Linneberg Allan A Melander Olle O Milani Lili L Neville Matt M Orho-Melander Marju M Qi Lu L Qi Qibin Q Roden Michael M Rolandsson Olov O Swift Amy A Rosengren Anders H AH Stirrups Kathleen K Wood Andrew R AR Mihailov Evelin E Blancher Christine C Carneiro Mauricio O MO Maguire Jared J Poplin Ryan R Shakir Khalid K Fennell Timothy T DePristo Mark M de Angelis Martin Hrabé MH Deloukas Panos P Gjesing Anette P AP Jun Goo G Nilsson Peter P Murphy Jacquelyn J Onofrio Robert R Thorand Barbara B Hansen Torben T Meisinger Christa C Hu Frank B FB Isomaa Bo B Karpe Fredrik F Liang Liming L Peters Annette A Huth Cornelia C O'Rahilly Stephen P SP Palmer Colin N A CNA Pedersen Oluf O Rauramaa Rainer R Tuomilehto Jaakko J Salomaa Veikko V Watanabe Richard M RM Syvänen Ann-Christine AC Bergman Richard N RN Bharadwaj Dwaipayan D Bottinger Erwin P EP Cho Yoon Shin YS Chandak Giriraj R GR Chan Juliana C N JCN Chia Kee Seng KS Daly Mark J MJ Ebrahim Shah B SB Langenberg Claudia C Elliott Paul P Jablonski Kathleen A KA Lehman Donna M DM Jia Weiping W Ma Ronald C W RCW Pollin Toni I TI Sandhu Manjinder M Tandon Nikhil N Froguel Philippe P Barroso Inês I Teo Yik Ying YY Zeggini Eleftheria E Loos Ruth J F RJF Small Kerrin S KS Ried Janina S JS DeFronzo Ralph A RA Grallert Harald H Glaser Benjamin B Metspalu Andres A Wareham Nicholas J NJ Walker Mark M Banks Eric E Gieger Christian C Ingelsson Erik E Im Hae Kyung HK Illig Thomas T Franks Paul W PW Buck Gemma G Trakalo Joseph J Buck David D Prokopenko Inga I Mägi Reedik R Lind Lars L Farjoun Yossi Y Owen Katharine R KR Gloyn Anna L AL Strauch Konstantin K Tuomi Tiinamaija T Kooner Jaspal Singh JS Lee Jong-Young JY Park Taesung T Donnelly Peter P Morris Andrew D AD Hattersley Andrew T AT Bowden Donald W DW Collins Francis S FS Atzmon Gil G Chambers John C JC Spector Timothy D TD Laakso Markku M Strom Tim M TM Bell Graeme I GI Blangero John J Duggirala Ravindranath R Tai E Shyong ES McVean Gilean G Hanis Craig L CL Wilson James G JG Seielstad Mark M Frayling Timothy M TM Meigs James B JB Cox Nancy J NJ Sladek Rob R Lander Eric S ES Gabriel Stacey S Burtt Noël P NP Mohlke Karen L KL Meitinger Thomas T Groop Leif L Abecasis Goncalo G Florez Jose C JC Scott Laura J LJ Morris Andrew P AP Kang Hyun Min HM Boehnke Michael M Altshuler David D McCarthy Mark I MI

Nature 20160711 7614

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed ...[more]

PMID: 27398621

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Project description:Biological traces recovered from crime scenes serve as vital evidence in forensic investigations. While DNA evidence is frequently used to address the sub-source level of the hierarchy of propositions, the biological source of the DNA can be highly probative at the source level. Current body fluid detection methods pose certain limitations, such as reports of false positive results from some of the presumptive and/or confirmatory tests in current use. These tests are also individual tests for the detection of one body fluid, meaning that if the sample is suspected to be a mixture of multiple body fluids, then different tests would need to be conducted to confirm the body fluid(s) present, which may exhaust small amounts of available biological trace. Proteomics applications for the identification of body fluids have been previously explored, and potential biomarkers indicative of body fluids discovered from liquid-chromatography tandem mass spectrometry (LC-MS/MS) methods have been reported. This work focuses on developing a mass spectrometry-based proteomics approach for the identification of body fluids by targeting discriminating peptide biomarkers from the non-DNA component left over after DNA extraction of samples. The non-DNA component is typically a waste product but with unappreciated evidential value. Our methodology for the purification of proteins from the post-DNA extraction waste includes an acetone precipitation and single-pot solid-phase-enhanced sample preparation (SP3) technique, microwave-assisted trypsin digestion, and LC-MS/MS analysis of the resultant peptides. Preliminary results from this proof-of-concept study include a list of potentially discriminating proteins and peptides for blood, saliva, and semen developed from the analysis of post-DNA extraction waste. Our method allows for multiple analytes to be targeted simultaneously from a DNA profiling waste stream and we anticipate that it could eventually be incorporated into standard forensic laboratory workflows.

Project description:Aims: Pathogenic truncating variants in the largest human protein TITIN are a leading cause of dilated cardiomyopathy. Because of the size of the gene encoding TITIN, many missense variations are identified. These are difficult to evaluate in genetic testing, as even individually rare variants are common in aggregate in normal populations. While the majority will be benign, a small subset is pathogenic, but distinction is challenging. Here, we describe the generation of a mouse model to investigate the underlying disease mechanism of a previously reported TITIN A178D missense variant identified in a family with non-compaction and dilated cardiomyopathy. Methods and Results: Heterozygous and homozygous mice carrying the TITIN A178D missense variant were characterised in vivo. Heterozygous mice had no detectable phenotype at any time point observed (up to 1 year). By contrast, homozygous mice developed dilated cardiomyopathy from 3 months. Chronic adrenergic stimulation aggravated the phenotype. Targeted transcript profiling revealed induction of the fetal gene programme and hypertrophic signalling pathways in homozygous mice, and these were confirmed at the protein level. Unsupervised proteomics identified down-regulation of TELETHONIN and FOUR-AND-A-HALF LIM DOMAIN 2, as well as the up-regulation of heat shock proteins and MYELOID LEUKEMIA FACTOR 1. Loss of TELETHONIN from the cardiac Z-disc was accompanied by proteasomal degradation; however, TELETHONIN also accumulated in the cytoplasm. In parallel, a proteo-toxic response was observed in the mice. Conclusions: We have shown that the TITIN A178D missense variant is pathogenic in homozygous mice, resulting in cardiomyopathy. We also provide evidence of the disease mechanism. Because the TITIN A178D variant abolishes binding of TELETHONIN, this leads to its abnormal cytoplasmic accumulation. Subsequent degradation of TELETHONIN by the proteasome results in proteasomal overload, and activation of a proteo-toxic response. The latter appears to be a driving factor for the cardiomyopathy observed in the mouse model.

Dataset Information

13K T2D-GENES analysis files

Publications

The genetic architecture of type 2 diabetes.

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