- Menu
2020
Authors
Aguet, F; Barbeira, AN; Bonazzola, R; Brown, A; Castel, SE; Jo, B; Kasela, S; Kim Hellmuth, S; Liang, Y; Oliva, M; Flynn, ED; Parsana, P; Fresard, L; Gamazon, ER; Hamel, AR; He, Y; Hormozdiari, F; Mohammadi, P; Muñoz Aguirre, M; Park, Y; Saha, A; Segrè, AV; Strober, BJ; Wen, X; Wucher, V; Ardlie, KG; Battle, A; Brown, CD; Cox, N; Das, S; Dermitzakis, ET; Engelhardt, BE; Garrido Martín, D; Gay, NR; Getz, GA; Guigó, R; Handsaker, RE; Hoffman, PJ; Im, HK; Kashin, S; Kwong, A; Lappalainen, T; Li, X; MacArthur, DG; Montgomery, SB; Rouhana, JM; Stephens, M; Stranger, BE; Todres, E; Viñuela, A; Wang, G; Zou, Y; Anand, S; Gabriel, S; Graubert, A; Hadley, K; Huang, KH; Meier, SR; Nedzel, JL; Nguyen, DT; Balliu, B; Conrad, DF; Cotter, DJ; deGoede, OM; Einson, J; Eskin, E; Eulalio, TY; Ferraro, NM; Gloudemans, MJ; Hou, L; Kellis, M; Li, X; Mangul, S; Nachun, DC; Nobel, AB; Park, Y; Rao, AS; Reverter, F; Sabatti, C; Skol, AD; Teran, NA; Wright, F; Ferreira, PG; Li, G; Melé, M; Yeger Lotem, E; Barcus, ME; Bradbury, D; Krubit, T; McLean, JA; Qi, L; Robinson, K; Roche, NV; Smith, AM; Sobin, L; Tabor, DE; Undale, A; Bridge, J; Brigham, LE; Foster, BA; Gillard, BM; Hasz, R; Hunter, M; Johns, C; Johnson, M; Karasik, E; Kopen, G; Leinweber, WF; McDonald, A; Moser, MT; Myer, K; Ramsey, KD; Roe, B; Shad, S; Thomas, JA; Walters, G; Washington, M; Wheeler, J; Jewell, SD; Rohrer, DC; Valley, DR; Davis, DA; Mash, DC; Branton, PA; Barker, LK; Gardiner, HM; Mosavel, M; Siminoff, LA; Flicek, P; Haeussler, M; Juettemann, T; Kent, WJ; Lee, CM; Powell, CC; Rosenbloom, KR; Ruffier, M; Sheppard, D; Taylor, K; Trevanion, SJ; Zerbino, DR; Abell, NS; Akey, J; Chen, L; Demanelis, K; Doherty, JA; Feinberg, AP; Hansen, KD; Hickey, PF; Jasmine, F; Jiang, L; Kaul, R; Kibriya, MG; Li, JB; Li, Q; Lin, S; Linder, SE; Pierce, BL; Rizzardi, LF; Smith, KS; Snyder, M; Stamatoyannopoulos, J; Tang, H; Wang, M; Carithers, LJ; Guan, P; Koester, SE; Little, AR; Moore, HM; Nierras, CR; Rao, AK; Vaught, JB; Volpi, S;
Publication
Science
Abstract
INTRODUCTION: The human genome contains tens of thousands of rare (minor allele frequency <1%) variants, some of which contribute to disease risk. Using 838 samples with whole-genome and multitissue transcriptome sequencing data in the Genotype-Tissue Expression (GTEx) project version 8, we assessed how rare genetic variants contribute to extreme patterns in gene expression (eOutliers), allelic expression (aseOutliers), and alternative splicing (sOutliers). We integrated these three signals across 49 tissues with genomic annotations to prioritize high-impact rare variants (RVs) that associate with human traits. RATIONALE: Outlier gene expression aids in identifying functional RVs. Transcriptome sequencing provides diverse measurements beyond gene expression, including allele-specific expression and alternative splicing, which can provide additional insight into RV functional effects. RESULTS: After identifying multitissue eOutliers, aseOutliers, and sOutliers, we found that outlier individuals of each type were significantly more likely to carry an RV near the corresponding gene. Among eOutliers, we observed strong enrichment of rare structural variants. sOutliers were particularly enriched for RVs that disrupted or created a splicing consensus sequence. aseOutliers provided the strongest enrichment signal when evaluated from just a single tissue. We developed Watershed, a probabilistic model for personal genome interpretation that improves over standard genomic annotation–based methods for scoring RVs by integrating these three transcriptomic signals from the same individual and replicates in an independent cohort. To assess whether outlier RVs identified in GTEx associate with traits, we evaluated these variants for association with diverse traits in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. We found that transcriptome-assisted prioritization identified RVs with larger trait effect sizes and were better predictors of effect size than genomic annotation alone. CONCLUSION: With >800 genomes matched with transcriptomes across 49 tissues, we were able to study RVs that underlie extreme changes in the transcriptome. To capture the diversity of these extreme changes, we developed and integrated approaches to identify expression, allele-specific expression, and alternative splicing outliers, and characterized the RV landscape underlying each outlier signal. We demonstrate that personal genome interpretation and RV discovery is enhanced by using these signals. This approach provides a new means to integrate a richer set of functional RVs into models of genetic burden, improve disease gene identification, and enable the delivery of precision genomics.
2021
Authors
Zurek, B; Ellwanger, K; Vissers, LELM; Schüle, R; Synofzik, M; Töpf, A; de Voer, RM; Laurie, S; Matalonga, L; Gilissen, C; Ossowski, S; ’t Hoen, PAC; Vitobello, A; Schulze Hentrich, JM; Riess, O; Brunner, HG; Brookes, AJ; Rath, A; Bonne, G; Gumus, G; Verloes, A; Hoogerbrugge, N; Evangelista, T; Harmuth, T; Swertz, M; Spalding, D; Hoischen, A; Beltran, S; Graessner, H; Haack, TB; Zurek, B; Ellwanger, K; Demidov, G; Sturm, M; Kessler, C; Wayand, M; Wilke, C; Traschütz, A; Schöls, L; Hengel, H; Heutink, P; Brunner, H; Scheffer, H; Steyaert, W; Sablauskas, K; de Voer, RM; Kamsteeg, E; van de Warrenburg, B; van Os, N; te Paske, I; Janssen, E; de Boer, E; Steehouwer, M; Yaldiz, B; Kleefstra, T; Veal, C; Gibson, S; Wadsley, M; Mehtarizadeh, M; Riaz, U; Warren, G; Dizjikan, FY; Shorter, T; Straub, V; Bettolo, CM; Specht, S; Clayton Smith, J; Banka, S; Alexander, E; Jackson, A; Faivre, L; Thauvin, C; Vitobello, A; Denommé Pichon, A; Duffourd, Y; Tisserant, E; Bruel, A; Peyron, C; Pélissier, A; Beltran, S; Gut, IG; Laurie, S; Piscia, D; Matalonga, L; Papakonstantinou, A; Bullich, G; Corvo, A; Garcia, C; Fernandez Callejo, M; Hernández, C; Picó, D; Paramonov, I; Lochmüller, H; Gumus, G; Bros Facer, V; Hanauer, M; Olry, A; Lagorce, D; Havrylenko, S; Izem, K; Rigour, F; Stevanin, G; Durr, A; Davoine, C; Guillot Noel, L; Heinzmann, A; Coarelli, G; Allamand, V; Nelson, I; Yaou, RB; Metay, C; Eymard, B; Cohen, E; Atalaia, A; Stojkovic, T; Macek, M; Turnovec, M; Thomasová, D; Kremliková, RP; Franková, V; Havlovicová, M; Kremlik, V; Parkinson, H; Keane, T; Senf, A; Robinson, P; Danis, D; Robert, G; Costa, A; Patch, C; Hanna, M; Houlden, H; Reilly, M; Vandrovcova, J; Muntoni, F; Zaharieva, I; Sarkozy, A; Timmerman, V; Baets, J; Van de Vondel, L; Beijer, D; de Jonghe, P; Nigro, V; Banfi, S; Torella, A; Musacchia, F; Piluso, G; Ferlini, A; Selvatici, R; Rossi, R; Neri, M; Aretz, S; Spier, I; Sommer, AK; Peters, S; Oliveira, C; Pelaez, JG; Matos, AR; José, CS; Ferreira, M; Gullo, I; Fernandes, S; Garrido, L; Ferreira, P; Carneiro, F; Swertz, MA; Johansson, L; van der Velde, JK; van der Vries, G; Neerincx, PB; Roelofs Prins, D; Köhler, S; Metcalfe, A; Verloes, A; Drunat, S; Rooryck, C; Trimouille, A; Castello, R; Morleo, M; Pinelli, M; Varavallo, A; De la Paz, MP; Sánchez, EB; Martín, EL; Delgado, BM; de la Rosa, FJAG; Ciolfi, A; Dallapiccola, B; Pizzi, S; Radio, FC; Tartaglia, M; Renieri, A; Benetti, E; Balicza, P; Molnar, MJ; Maver, A; Peterlin, B; Münchau, A; Lohmann, K; Herzog, R; Pauly, M; Macaya, A; Marcé Grau, A; Osorio, AN; de Benito, DN; Lochmüller, H; Thompson, R; Polavarapu, K; Beeson, D; Cossins, J; Cruz, PMR; Hackman, P; Johari, M; Savarese, M; Udd, B; Horvath, R; Capella, G; Valle, L; Holinski Feder, E; Laner, A; Steinke Lange, V; Schröck, E; Rump, A;
Publication
EUROPEAN JOURNAL OF HUMAN GENETICS
Abstract
For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient’s data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe.
2021
Authors
Schüle, R; Timmann, D; Erasmus, CE; Reichbauer, J; Wayand, M; Baets, J; Balicza, P; Chinnery, P; Dürr, A; Haack, T; Hengel, H; Horvath, R; Houlden, H; Kamsteeg, E; Kamsteeg, C; Lohmann, K; Macaya, A; Marcé Grau, A; Maver, A; Molnar, J; Münchau, A; Peterlin, B; Riess, O; Schöls, L; Schüle, R; Stevanin, G; Synofzik, M; Timmerman, V; van de Warrenburg, B; van Os, N; Vandrovcova, J; Wayand, M; Wilke, C; van de Warrenburg, B; Schöls, L; Wilke, C; Bevot, A; Zuchner, S; Beltran, S; Laurie, S; Matalonga, L; Graessner, H; Synofzik, M; Graessner, H; Zurek, B; Ellwanger, K; Ossowski, S; Demidov, G; Sturm, M; Schulze Hentrich, JM; Heutink, P; Brunner, H; Scheffer, H; Hoogerbrugge, N; Hoischen, A; ’t Hoen, PAC; Vissers, LELM; Gilissen, C; Steyaert, W; Sablauskas, K; de Voer, RM; Janssen, E; de Boer, E; Steehouwer, M; Yaldiz, B; Kleefstra, T; Brookes, AJ; Veal, C; Gibson, S; Wadsley, M; Mehtarizadeh, M; Riaz, U; Warren, G; Dizjikan, FY; Shorter, T; Töpf, A; Straub, V; Bettolo, CM; Specht, S; Clayton Smith, J; Banka, S; Alexander, E; Jackson, A; Faivre, L; Thauvin, C; Vitobello, A; Denommé Pichon, A; Duffourd, Y; Tisserant, E; Bruel, A; Peyron, C; Pélissier, A; Beltran, S; Gut, IG; Laurie, S; Piscia, D; Matalonga, L; Papakonstantinou, A; Bullich, G; Corvo, A; Garcia, C; Fernandez Callejo, M; Hernández, C; Picó, D; Paramonov, I; Lochmüller, H; Gumus, G; Bros Facer, V; Rath, A; Hanauer, M; Olry, A; Lagorce, D; Havrylenko, S; Izem, K; Rigour, F; Durr, A; Davoine, C; Guillot Noel, L; Heinzmann, A; Coarelli, G; Bonne, G; Evangelista, T; Allamand, V; Nelson, I; Yaou, RB; Metay, C; Eymard, B; Cohen, E; Atalaia, A; Stojkovic, T; Macek, M; Turnovec, M; Thomasová, D; Kremliková, RP; Franková, V; Havlovicová, M; Kremlik, V; Parkinson, H; Keane, T; Spalding, D; Senf, A; Robinson, P; Danis, D; Robert, G; Costa, A; Patch, C; Hanna, M; Houlden, H; Reilly, M; Vandrovcova, J; Muntoni, F; Zaharieva, I; Sarkozy, A; de Jonghe, P; Nigro, V; Banfi, S; Torella, A; Musacchia, F; Piluso, G; Ferlini, A; Selvatici, R; Rossi, R; Neri, M; Aretz, S; Spier, I; Sommer, AK; Peters, S; Oliveira, C; Pelaez, JG; Matos, AR; José, CS; Ferreira, M; Gullo, I; Fernandes, S; Garrido, L; Ferreira, P; Carneiro, F; Swertz, MA; Johansson, L; van der Velde, JK; van der Vries, G; Neerincx, PB; Roelofs Prins, D; Köhler, S; Metcalfe, A; Verloes, A; Drunat, S; Rooryck, C; Trimouille, A; Castello, R; Morleo, M; Pinelli, M; Varavallo, A; De la Paz, MP; Sánchez, EB; Martín, EL; Delgado, BM; de la Rosa, FJAG; Ciolfi, A; Dallapiccola, B; Pizzi, S; Radio, FC; Tartaglia, M; Renieri, A; Benetti, E; Balicza, P; Molnar, MJ; Maver, A; Peterlin, B; Münchau, A; Lohmann, K; Herzog, R; Pauly, M; Macaya, A; Marcé Grau, A; Osorio, AN; de Benito, DN; Lochmüller, H; Thompson, R; Polavarapu, K; Beeson, D; Cossins, J; Cruz, PMR; Hackman, P; Johari, M; Savarese, M; Udd, B; Horvath, R; Capella, G; Valle, L; Holinski Feder, E; Laner, A; Steinke Lange, V; Schröck, E; Rump, A;
Publication
EUROPEAN JOURNAL OF HUMAN GENETICS
Abstract
2020
Authors
Castel S.E.; Aguet F.; Aguet F.; Aguet F.; Mohammadi P.; Mohammadi P.; Anand S.; Anand S.; Ardlie K.G.; Ardlie K.G.; Gabriel S.; Getz G.A.; Graubert A.; Graubert A.; Hadley K.; Hadley K.; Handsaker R.E.; Handsaker R.E.; Huang K.H.; Kashin S.; Kashin S.; Li X.; MacArthur D.G.; Meier S.R.; Meier S.R.; Nedzel J.L.; Nedzel J.L.; Nguyen D.T.; Segrè A.V.; Todres E.; Todres E.; Balliu B.; Barbeira A.N.; Battle A.; Bonazzola R.; Brown A.; Brown C.D.; Castel S.E.; Conrad D.F.; Cotter D.J.; Cox N.; Das S.; De Goede O.M.; Dermitzakis E.T.; Einson J.; Engelhardt B.E.; Eskin E.; Eulalio T.Y.; Ferraro N.M.; Flynn E.D.; Fresard L.; Gamazon E.R.; Garrido-Martín D.; Gay N.R.; Gloudemans M.J.; Guigó R.; Hame A.R.; He Y.; Hoffman P.J.; Hormozdiari F.; Hou L.; Huang K.H.; Im H.K.; Jo B.; Kasela S.; Kellis M.; Kim-Hellmuth S.; Kwong A.; Lappalainen T.; Li X.; Li X.; Liang Y.; Mangul S.; Montgomery S.B.; Muñoz-Aguirre M.; Nachun D.C.; Nguyen D.T.; Nobel A.B.; Oliva M.; Park Y.S.; Park Y.; Parsana P.; Rao A.S.; Reverter F.; Rouhana J.M.; Sabatti C.; Saha A.; Segrè A.V.; Skol A.D.; Stephens M.; Stranger B.E.; Strober B.J.; Teran N.A.; Viñuela A.; Wang G.; Wen X.; Wright F.; Wucher V.; Zou Y.; Ferreira P.G.;
Publication
Genome Biology
Abstract
Allele expression (AE) analysis robustly measures cis-regulatory effects. Here, we present and demonstrate the utility of a vast AE resource generated from the GTEx v8 release, containing 15,253 samples spanning 54 human tissues for a total of 431 million measurements of AE at the SNP level and 153 million measurements at the haplotype level. In addition, we develop an extension of our tool phASER that allows effect sizes of cis-regulatory variants to be estimated using haplotype-level AE data. This AE resource is the largest to date, and we are able to make haplotype-level data publicly available. We anticipate that the availability of this resource will enable future studies of regulatory variation across human tissues.
2018
Authors
Rocha, M; Ferreira, PG;
Publication
Bioinformatics Algorithms: Design and Implementation in Python
Abstract
Bioinformatics Algorithms: Design and Implementation in Python provides a comprehensive book on many of the most important bioinformatics problems, putting forward the best algorithms and showing how to implement them. The book focuses on the use of the Python programming language and its algorithms, which is quickly becoming the most popular language in the bioinformatics field. Readers will find the tools they need to improve their knowledge and skills with regard to algorithm development and implementation, and will also uncover prototypes of bioinformatics applications that demonstrate the main principles underlying real world applications.
2021
Authors
Schüle, R; Timmann, D; Erasmus, CE; Reichbauer, J; Wayand, M; Baets, J; Balicza, P; Chinnery, P; Dürr, A; Haack, T; Hengel, H; Horvath, R; Houlden, H; Kamsteeg, EJ; Kamsteeg, C; Lohmann, K; Macaya, A; Marcé Grau, A; Maver, A; Molnar, J; Münchau, A; Peterlin, B; Riess, O; Schöls, L; Schüle, R; Stevanin, G; Synofzik, M; Timmerman, V; van de Warrenburg, B; van Os, N; Vandrovcova, J; Wayand, M; Wilke, C; van de Warrenburg, B; Schöls, L; Wilke, C; Bevot, A; Zuchner, S; Beltran, S; Laurie, S; Matalonga, L; Graessner, H; Synofzik, M; Graessner, H; Zurek, B; Ellwanger, K; Ossowski, S; Demidov, G; Sturm, M; Schulze Hentrich, JM; Heutink, P; Brunner, H; Scheffer, H; Hoogerbrugge, N; Hoischen, A; ’t Hoen, PAC; Vissers, LELM; Gilissen, C; Steyaert, W; Sablauskas, K; de Voer, RM; Janssen, E; de Boer, E; Steehouwer, M; Yaldiz, B; Kleefstra, T; Brookes, AJ; Veal, C; Gibson, S; Wadsley, M; Mehtarizadeh, M; Riaz, U; Warren, G; Dizjikan, FY; Shorter, T; Töpf, A; Straub, V; Bettolo, CM; Specht, S; Clayton Smith, J; Banka, S; Alexander, E; Jackson, A; Faivre, L; Thauvin, C; Vitobello, A; Denommé Pichon, AS; Duffourd, Y; Tisserant, E; Bruel, AL; Peyron, C; Pélissier, A; Beltran, S; Gut, IG; Laurie, S; Piscia, D; Matalonga, L; Papakonstantinou, A; Bullich, G; Corvo, A; Garcia, C; Fernandez Callejo, M; Hernández, C; Picó, D; Paramonov, I; Lochmüller, H; Gumus, G; Bros Facer, V; Rath, A; Hanauer, M; Olry, A; Lagorce, D; Havrylenko, S; Izem, K; Rigour, F; Durr, A; Davoine, CS; Guillot Noel, L; Heinzmann, A; Coarelli, G; Bonne, G; Evangelista, T; Allamand, V; Nelson, I; Yaou, RB; Metay, C; Eymard, B; Cohen, E; Atalaia, A; Stojkovic, T; Macek, M; Turnovec, M; Thomasová, D; Kremliková, RP; Franková, V; Havlovicová, M; Kremlik, V; Parkinson, H; Keane, T; Spalding, D; Senf, A; Robinson, P; Danis, D; Robert, G; Costa, A; Patch, C; Hanna, M; Houlden, H; Reilly, M; Vandrovcova, J; Muntoni, F; Zaharieva, I; Sarkozy, A; de Jonghe, P; Nigro, V; Banfi, S; Torella, A; Musacchia, F; Piluso, G; Ferlini, A; Selvatici, R; Rossi, R; Neri, M; Aretz, S; Spier, I; Sommer, AK; Peters, S; Oliveira, C; Pelaez, JG; Matos, AR; José, CS; Ferreira, M; Gullo, I; Fernandes, S; Garrido, L; Ferreira, P; Carneiro, F; Swertz, MA; Johansson, L; van der Velde, JK; van der Vries, G; Neerincx, PB; Roelofs Prins, D; Köhler, S; Metcalfe, A; Verloes, A; Drunat, S; Rooryck, C; Trimouille, A; Castello, R; Morleo, M; Pinelli, M; Varavallo, A; De la Paz, MP; Sánchez, EB; Martín, EL; Delgado, BM; de la Rosa, FJAG; Ciolfi, A; Dallapiccola, B; Pizzi, S; Radio, FC; Tartaglia, M; Renieri, A; Benetti, E; Balicza, P; Molnar, MJ; Maver, A; Peterlin, B; Münchau, A; Lohmann, K; Herzog, R; Pauly, M; Macaya, A; Marcé Grau, A; Osorio, AN; de Benito, DN; Lochmüller, H; Thompson, R; Polavarapu, K; Beeson, D; Cossins, J; Cruz, PMR; Hackman, P; Johari, M; Savarese, M; Udd, B; Horvath, R; Capella, G; Valle, L; Holinski Feder, E; Laner, A; Steinke Lange, V; Schröck, E; Rump, A;
Publication
European Journal of Human Genetics
Abstract
In the original publication of the article, consortium author lists were missing in the article. © 2021, The Author(s).
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