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TABLE OF CONTENTS | August 2017 Volume 49, Issue 8 | | | | | Editorial News and Views Analysis Articles Letters Erratum Corrigenda
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REGISTER NOW! | | | | | | Editorial | Top | | | | Necessary complexity p1161 doi:10.1038/ng.3932 This month's research articles span the range of scales of gene-regulatory mechanisms, from a deceptively simple gene therapy vector, via synthetic gene expression circuits, to extremely intricate epigenetic switches. We encourage investigation of synthetic circuits exploring the functions of the 3D genome.
| | News and Views | Top | | | | | | Analysis | Top | | | | The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability pp1167 - 1173 Tarjinder Singh, James T R Walters, Mandy Johnstone, David Curtis, Jaana Suvisaari, Minna Torniainen, Elliott Rees, Conrad Iyegbe, Douglas Blackwood, Andrew M McIntosh, Georg Kirov, Daniel Geschwind, Robin M Murray, Marta Di Forti, Elvira Bramon, Michael Gandal, Christina M Hultman, Pamela Sklar, INTERVAL Study, UK10K Consortium, Aarno Palotie, Patrick F Sullivan, Michael C O'Donovan, Michael J Owen & Jeffrey C Barrett doi:10.1038/ng.3903 Jeffrey Barrett, Tarjinder Singh and colleagues present a meta-analysis of rare coding variants and copy number variants in a large collection of schizophrenia cases and controls, combined with de novo mutation data from family trios. They find that rare, damaging variants contribute to risk of schizophrenia both with and without intellectual disability and that there is overlap between genetic risk for schizophrenia and other neurodevelopmental disorders.
| | | | Genotype-covariate interaction effects and the heritability of adult body mass index pp1174 - 1181 Matthew R Robinson, Geoffrey English, Gerhard Moser, Luke R Lloyd-Jones, Marcus A Triplett, Zhihong Zhu, Ilja M Nolte, Jana V van Vliet-Ostaptchouk, Harold Snieder, The LifeLines Cohort Study, Tonu Esko, Lili Milani, Reedik Mägi, Andres Metspalu, Patrik K E Magnusson, Nancy L Pedersen, Erik Ingelsson, Magnus Johannesson, Jian Yang, David Cesarini & Peter M Visscher doi:10.1038/ng.3912 Matthew Robinson, Peter Visscher and colleagues use phenotypic data on 172,000 sibling pairs and phenotypic and SNP data on 150,832 unrelated individuals to estimate the heritability of body mass index across a range of experimental designs. They conclude that substantially larger sample sizes across ages and lifestyle factors will be required to understand the full genetic architecture of this trait.
| | Advertisement | | npj Molecular Phenomics is an online-only, open access journal that provides a forum for cutting-edge scientific advances in the emerging field of phenomics, the study of the physical and chemical characteristics of an individual in quantitative terms.
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Find out more >> | | | | | | Articles | Top | | | | Identification of sequence variants influencing immunoglobulin levels pp1182 - 1191 Stefan Jonsson, Gardar Sveinbjornsson, Aitzkoa Lopez de Lapuente Portilla, Bhairavi Swaminathan, Rosina Plomp, Gillian Dekkers, Ram Ajore, Mina Ali, Arthur E H Bentlage, Evelina Elmér, Gudmundur I Eyjolfsson, Sigurjon A Gudjonsson, Urban Gullberg, Arnaldur Gylfason, Bjarni V Halldorsson, Markus Hansson, Hilma Holm, Åsa Johansson, Ellinor Johnsson, Aslaug Jonasdottir, Bjorn R Ludviksson, Asmundur Oddsson, Isleifur Olafsson, Sigurgeir Olafsson, Olof Sigurdardottir, Asgeir Sigurdsson, Lilja Stefansdottir, Gisli Masson, Patrick Sulem, Manfred Wuhrer, Anna-Karin Wihlborg, Gudmar Thorleifsson, Daniel F Gudbjartsson, Unnur Thorsteinsdottir, Gestur Vidarsson, Ingileif Jonsdottir, Björn Nilsson & Kari Stefansson doi:10.1038/ng.3897 Ingileif Jonsdottir, Björn Nilsson, Kari Stefansson and colleagues perform a genome-wide association study for immunoglobulin levels in Icelandic and Swedish cohorts. They find 38 new variants associated with IgA, IgG, IgM or composite immunoglobulin traits and identify candidate genes underlying the regulation of immunoglobulin levels.
| | | | Germline hypomorphic CARD11 mutations in severe atopic disease pp1192 - 1201 Chi A Ma, Jeffrey R Stinson, Yuan Zhang, Jordan K Abbott, Michael A Weinreich, Pia J Hauk, Paul R Reynolds, Jonathan J Lyons, Celeste G Nelson, Elisa Ruffo, Batsukh Dorjbal, Salomé Glauzy, Natsuko Yamakawa, Swadhinya Arjunaraja, Kelsey Voss, Jennifer Stoddard, Julie Niemela, Yu Zhang, Sergio D Rosenzweig, Joshua J McElwee, Thomas DiMaggio, Helen F Matthews, Nina Jones, Kelly D Stone, Alejandro Palma, Matías Oleastro, Emma Prieto, Andrea R Bernasconi, Geronimo Dubra, Silvia Danielian, Jonathan Zaiat, Marcelo A Marti, Brian Kim, Megan A Cooper, Neil Romberg, Eric Meffre, Erwin W Gelfand, Andrew L Snow & Joshua D Milner doi:10.1038/ng.3898 Erwin Gelfand, Andrew Snow, Joshua Milner and colleagues identify heterozygous CARD11 mutations associated with severe atopic disease in eight individuals from four families. They further show that the mutant CARD11 proteins exhibit both loss-of-function and dominant-interfering activity and that the cellular defects in patient T cells can be partially rescued by supplementing with glutamine.
See also: News and Views by Biggs et al.
| | | | Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk pp1202 - 1210 Terence D Capellini, Hao Chen, Jiaxue Cao, Andrew C Doxey, Ata M Kiapour, Michael Schoor & David M Kingsley doi:10.1038/ng.3911 Terence Capellini, David Kingsley and colleagues use transgenic mice to show that a Gdf5 enhancer (termed GROW1) is required for normal bone length. They suggest that a common variant at the human GROW1 enhancer was under selection in human populations and also contributes to arthritis susceptibility.
See also: News and Views by Lettre
| | | | The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia pp1211 - 1218 Yu Liu, John Easton, Ying Shao, Jamie Maciaszek, Zhaoming Wang, Mark R Wilkinson, Kelly McCastlain, Michael Edmonson, Stanley B Pounds, Lei Shi, Xin Zhou, Xiaotu Ma, Edgar Sioson, Yongjin Li, Michael Rusch, Pankaj Gupta, Deqing Pei, Cheng Cheng, Malcolm A Smith, Jaime Guidry Auvil, Daniela S Gerhard, Mary V Relling, Naomi J Winick, Andrew J Carroll, Nyla A Heerema, Elizabeth Raetz, Meenakshi Devidas, Cheryl L Willman, Richard C Harvey, William L Carroll, Kimberly P Dunsmore, Stuart S Winter, Brent L Wood, Brian P Sorrentino, James R Downing, Mignon L Loh, Stephen P Hunger, Jinghui Zhang & Charles G Mullighan doi:10.1038/ng.3909 Charles Mullighan, Stephen Hunger, Jinghui Zhang and colleagues report a genomic analysis of 264 pediatric and young adult T-lineage acute lymphoblastic leukemia (T-ALL) samples. They identify 106 candidate driver genes, 53 of which have not been described previously in pediatric T-ALL, as well as associations between mutations and disease stage or subtype.
| | | | Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma pp1219 - 1230 Sjors M Kas, Julian R de Ruiter, Koen Schipper, Stefano Annunziato, Eva Schut, Sjoerd Klarenbeek, Anne Paulien Drenth, Eline van der Burg, Christiaan Klijn, Jelle J ten Hoeve, David J Adams, Marco J Koudijs, Jelle Wesseling, Micha Nethe, Lodewyk F A Wessels & Jos Jonkers doi:10.1038/ng.3905 Jos Jonkers, Lodewyk Wessels and colleagues use a Sleeping Beauty transposon mutagenesis screen to identify genes required for invasive lobular breast carcinoma formation (ILC) in mice. They find recurrent and mutually exclusive insertions in Myh9, Ppp1r12a, Ppp1r12b and Trp53bp2, which are implicated in the actin cytoskeleton regulation pathway and have been found to be altered in human ILC breast cancer.
| | | | Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium pp1231 - 1238 Terrence F Meehan, Nathalie Conte, David B West, Julius O Jacobsen, Jeremy Mason, Jonathan Warren, Chao-Kung Chen, Ilinca Tudose, Mike Relac, Peter Matthews, Natasha Karp, Luis Santos, Tanja Fiegel, Natalie Ring, Henrik Westerberg, Simon Greenaway, Duncan Sneddon, Hugh Morgan, Gemma F Codner, Michelle E Stewart, James Brown, Neil Horner, The International Mouse Phenotyping Consortium, Melissa Haendel, Nicole Washington, Christopher J Mungall, Corey L Reynolds, Juan Gallegos, Valerie Gailus-Durner, Tania Sorg, Guillaume Pavlovic, Lynette R Bower, Mark Moore, Iva Morse, Xiang Gao, Glauco P Tocchini-Valentini, Yuichi Obata, Soo Young Cho, Je Kyung Seong, John Seavitt, Arthur L Beaudet, Mary E Dickinson, Yann Herault, Wolfgang Wurst, Martin Hrabe de Angelis, K C Kent Lloyd, Ann M Flenniken, Lauryl M J Nutter, Susan Newbigging, Colin McKerlie, Monica J Justice, Stephen A Murray, Karen L Svenson, Robert E Braun, Jacqueline K White, Allan Bradley, Paul Flicek, Sara Wells, William C Skarnes, David J Adams, Helen Parkinson, Ann-Marie Mallon, Steve D M Brown & Damian Smedley doi:10.1038/ng.3901 Damian Smedley and colleagues report the phenotypic characterization of the first 3,328 genes by the International Mouse Phenotyping Consortium. They develop new mouse models based on genes known to be associated with human mendelian diseases and identify potential disease-associated genes with little or no previous functional annotation.
| | | | The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain pp1239 - 1250 Yan Jiang, Yong-Hwee Eddie Loh, Prashanth Rajarajan, Teruyoshi Hirayama, Will Liao, Bibi S Kassim, Behnam Javidfar, Brigham J Hartley, Lisa Kleofas, Royce B Park, Benoit Labonte, Seok-Man Ho, Sandhya Chandrasekaran, Catherine Do, Brianna R Ramirez, Cyril J Peter, Julia T C W, Brian M Safaie, Hirofumi Morishita, Panos Roussos, Eric J Nestler, Anne Schaefer, Benjamin Tycko, Kristen J Brennand, Takeshi Yagi, Li Shen & Schahram Akbarian doi:10.1038/ng.3906 Schahram Akbarian and colleagues report that mutation of the gene encoding the SETDB1 (KMT1E) histone methyltransferase in mouse neurons leads to dissolution of chromosome conformations and a topologically associated domain at the clustered protocadherin locus. They show that SETDB1 prevents excess CTCF binding and is important for maintaining developmentally important higher-order chromatin organization.
| | Advertisement | | | | | Letters | Top | | | | Truncating mutations in RBM12 are associated with psychosis pp1251 - 1254 Stacy Steinberg, Steinunn Gudmundsdottir, Gardar Sveinbjornsson, Jaana Suvisaari, Tiina Paunio, Minna Torniainen-Holm, Michael L Frigge, Gudrun A Jonsdottir, Johanna Huttenlocher, Sunna Arnarsdottir, Oddur Ingimarsson, Magnus Haraldsson, Thorarinn Tyrfingsson, Thorgeir E Thorgeirsson, Augustine Kong, Gudmundur L Norddahl, Daniel F Gudbjartsson, Engilbert Sigurdsson, Hreinn Stefansson & Kari Stefansson doi:10.1038/ng.3894 Kari Stefansson and colleagues identify a nonsense mutation in RBM12 segregating with psychosis in an extended Icelandic pedigree and an independent frameshift mutation in RBM12 segregating with psychosis in a Finnish family. They further show that carriers of the Icelandic mutation who are unaffected by psychosis exhibit a psychiatric disorder and cognitive test battery profile resembling that of patients with schizophrenia.
| | | | Variants in the fetal genome near FLT1 are associated with risk of preeclampsia pp1255 - 1260 Ralph McGinnis, Valgerdur Steinthorsdottir, Nicholas O Williams, Gudmar Thorleifsson, Scott Shooter, Sigrun Hjartardottir, Suzannah Bumpstead, Lilja Stefansdottir, Lucy Hildyard, Jon K Sigurdsson, John P Kemp, Gabriela B Silva, Liv Cecilie V Thomsen, Tiina Jääskeläinen, Eero Kajantie, Sally Chappell, Noor Kalsheker, Ashley Moffett, Susan Hiby, Wai Kwong Lee, Sandosh Padmanabhan, Nigel A B Simpson, Vivien A Dolby, Eleonora Staines-Urias, Stephanie M Engel, Anita Haugan, Lill Trogstad, Gulnara Svyatova, Nodira Zakhidova, Dilbar Najmutdinova, The FINNPEC Consortium, The GOPEC Consortium, Anna F Dominiczak, Håkon K Gjessing, Juan P Casas, Frank Dudbridge, James J Walker, Fiona Broughton Pipkin, Unnur Thorsteinsdottir, Reynir T Geirsson, Debbie A Lawlor, Ann-Charlotte Iversen, Per Magnus, Hannele Laivuori, Kari Stefansson & Linda Morgan doi:10.1038/ng.3895 Ralph McGinnis, Valgerdur Steinthorsdottir, Linda Morgan and colleagues perform a genome-wide association study in the offspring of preeclampsia pregnancies and identify variants in the fetal genome near FLT1 that are associated with risk of preeclampsia. FLT1 is known to encode an isoform of placental origin implicated in the pathology of preeclampsia, providing biological support for the association of this locus with preeclampsia risk.
| | | | Neuroblastoma is composed of two super-enhancer-associated differentiation states pp1261 - 1266 Tim van Groningen, Jan Koster, Linda J Valentijn, Danny A Zwijnenburg, Nurdan Akogul, Nancy E Hasselt, Marloes Broekmans, Franciska Haneveld, Natalia E Nowakowska, Johannes Bras, Carel J M van Noesel, Aldo Jongejan, Antoine H van Kampen, Linda Koster, Frank Baas, Lianne van Dijk-Kerkhoven, Margriet Huizer-Smit, Maria C Lecca, Alvin Chan, Arjan Lakeman, Piet Molenaar, Richard Volckmann, Ellen M Westerhout, Mohamed Hamdi, Peter G van Sluis, Marli E Ebus, Jan J Molenaar, Godelieve A Tytgat, Bart A Westerman, Johan van Nes & Rogier Versteeg doi:10.1038/ng.3899 Rogier Versteeg, Johan van Nes and colleagues report that neuroblastomas comprise two cell types, mesenchymal and adrenergic, that have different responses to chemotherapeutic agents in vitro. Using ChIP-seq and expression profiling of pairs of phenotypically divergent isogenic cell lines, they identify candidate transcription factors for regulation of the two cell states.
| | | | Identification of liver-specific enhancer-promoter activity in the 3′ untranslated region of the wild-type AAV2 genome pp1267 - 1273 Grant J Logan, Allison P Dane, Claus V Hallwirth, Christine M Smyth, Emilie E Wilkie, Anais K Amaya, Erhua Zhu, Neeta Khandekar, Samantha L Ginn, Sophia H Y Liao, Sharon C Cunningham, Natsuki Sasaki, Martí Cabanes-Creus, Patrick P L Tam, David W Russell, Leszek Lisowski & Ian E Alexander doi:10.1038/ng.3893 Ian Alexander and colleagues characterize a liver-specific enhancer-promoter element that is found in the genome of wild-type adeno-associated virus type 2 (AAV2), from which gene transfer vectors have been derived. They suggest that these sequences could provide a possible link between AAV integration events in the liver and gene dysregulation and pathogenesis.
| | | | Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia pp1274 - 1281 Masafumi Seki, Shunsuke Kimura, Tomoya Isobe, Kenichi Yoshida, Hiroo Ueno, Yaeko Nakajima-Takagi, Changshan Wang, Lin Lin, Ayana Kon, Hiromichi Suzuki, Yusuke Shiozawa, Keisuke Kataoka, Yoichi Fujii, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Teppei Shimamura, Kyoko Masuda, Hiroshi Kawamoto, Kentaro Ohki, Motohiro Kato, Yuki Arakawa, Katsuyoshi Koh, Ryoji Hanada, Hiroshi Moritake, Masaharu Akiyama, Ryoji Kobayashi, Takao Deguchi, Yoshiko Hashii, Toshihiko Imamura, Atsushi Sato, Nobutaka Kiyokawa, Akira Oka, Yasuhide Hayashi, Masatoshi Takagi, Atsushi Manabe, Akira Ohara, Keizo Horibe, Masashi Sanada, Atsushi Iwama, Hiroyuki Mano, Satoru Miyano, Seishi Ogawa & Junko Takita doi:10.1038/ng.3900 Junko Takita, Seishi Ogawa and colleagues profile 121 cases of pediatric T cell acute lymphoblasic leukemia (T-ALL) and identify recurrent SPI1 (PU.1) gene fusions. They find that these SPI1 fusions correlated with poor survival, retained transcriptional activity and, in a mouse stem cell model, enhanced cell proliferation.
| | | | Synchronized DNA cycling across a bacterial population pp1282 - 1285 Leo Baumgart, William Mather & Jeff Hasty doi:10.1038/ng.3915 Jeff Hasty and colleagues use an endonuclease from S. cerevisiae along with quorum sensing from A. fischeri to produce sustained cycling of DNA plasmid concentration across a colony of E. coli cells. This copy number modulation system enables dynamic regulation of gene circuit elements without the need for specially engineered promoters.
See also: News and Views by Wu & You
| | | Erratum | Top | | | | Erratum: Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation p1286 Ingrid E Christophersen, Michiel Rienstra, Carolina Roselli, Xiaoyan Yin, Bastiaan Geelhoed, John Barnard, Honghuang Lin, Dan E Arking, Albert V Smith, Christine M Albert, Mark Chaffin, Nathan R Tucker, Molong Li, Derek Klarin, Nathan A Bihlmeyer, Siew-Kee Low, Peter E Weeke, Martina Müller-Nurasyid, J Gustav Smith, Jennifer A Brody, Maartje N Niemeijer, Marcus Dörr, Stella Trompet, Jennifer Huffman, Stefan Gustafsson, Claudia Schurmann, Marcus E Kleber, Leo-Pekka Lyytikäinen, Ilkka Seppälä, Rainer Malik, Andrea R V R Horimoto, Marco Perez, Juha Sinisalo, Stefanie Aeschbacher, Sébastien Thériault, Jie Yao, Farid Radmanesh, Stefan Weiss, Alexander Teumer, Seung Hoan Choi, Lu-Chen Weng, Sebastian Clauss, Rajat Deo, Daniel J Rader, Svati H Shah, Albert Sun, Jemma C Hopewell, Stephanie Debette, Ganesh Chauhan, Qiong Yang, Bradford B Worrall, Guillaume Paré, Yoichiro Kamatani, Yanick P Hagemeijer, Niek Verweij, Joylene E Siland, Michiaki Kubo, Jonathan D Smith, David R Van Wagoner, Joshua C Bis, Siegfried Perz, Bruce M Psaty, Paul M Ridker, Jared W Magnani, Tamara B Harris, Lenore J Launer, M Benjamin Shoemaker, Sandosh Padmanabhan, Jeffrey Haessler, Traci M Bartz, Melanie Waldenberger, Peter Lichtner, Marina Arendt, Jose E Krieger, Mika Kähönen, Lorenz Risch, Alfredo J Mansur, Annette Peters, Blair H Smith, Lars Lind, Stuart A Scott, Yingchang Lu, Erwin B Bottinger, Jussi Hernesniemi, Cecilia M Lindgren, Jorge A Wong, Jie Huang, Markku Eskola, Andrew P Morris, Ian Ford, Alex P Reiner, Graciela Delgado, Lin Y Chen, Yii-Der Ida Chen, Roopinder K Sandhu, Man Li, Eric Boerwinkle, Lewin Eisele, Lars Lannfelt, Natalia Rost, Christopher D Anderson, Kent D Taylor, Archie Campbell, Patrik K Magnusson, David Porteous, Lynne J Hocking, Efthymia Vlachopoulou, Nancy L Pedersen, Kjell Nikus, Marju Orho-Melander, Anders Hamsten, Jan Heeringa, Joshua C Denny, Jennifer Kriebel, Dawood Darbar, Christopher Newton-Cheh, Christian Shaffer, Peter W Macfarlane, Stefanie Heilmann-Heimbach, Peter Almgren, Paul L Huang, Nona Sotoodehnia, Elsayed Z Soliman, Andre G Uitterlinden, Albert Hofman, Oscar H Franco, Uwe Völker, Karl-Heinz Jöckel, Moritz F Sinner, Henry J Lin, Xiuqing Guo, METASTROKE Consortium of the ISGC, Neurology Working Group of the CHARGE Consortium, Martin Dichgans, Erik Ingelsson, Charles Kooperberg, Olle Melander, Ruth J F Loos, Jari Laurikka, David Conen, Jonathan Rosand, Pim van der Harst, Marja-Liisa Lokki, Sekar Kathiresan, Alexandre Pereira, J Wouter Jukema, Caroline Hayward, Jerome I Rotter, Winfried März, Terho Lehtimäki, Bruno H Stricker, Mina K Chung, Stephan B Felix, Vilmundur Gudnason, Alvaro Alonso, Dan M Roden, Stefan Kääb, Daniel I Chasman, Susan R Heckbert, Emelia J Benjamin, Toshihiro Tanaka, Kathryn L Lunetta, Steven A Lubitz, Patrick T Ellinor & for the AFGen Consortium doi:10.1038/ng0817-1286c
| Corrigenda | Top | | | | Corrigendum: Protein-structure-guided discovery of functional mutations across 19 cancer types p1286 Beifang Niu, Adam D Scott, Sohini Sengupta, Matthew H Bailey, Prag Batra, Jie Ning, Matthew A Wyczalkowski, Wen-Wei Liang, Qunyuan Zhang, Michael D McLellan, Sam Q Sun, Piyush Tripathi, Carolyn Lou, Kai Ye, R Jay Mashl, John Wallis, Michael C Wendl, Feng Chen & Li Ding doi:10.1038/ng0817-1286a
| | | | Corrigendum: Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis p1286 Unnur Styrkarsdottir, Hannes Helgason, Asgeir Sigurdsson, Gudmundur L Norddahl, Arna B Agustsdottir, Louise N Reynard, Amanda Villalvilla, Gisli H Halldorsson, Aslaug Jonasdottir, Audur Magnusdottir, Asmundur Oddson, Gerald Sulem, Florian Zink, Gardar Sveinbjornsson, Agnar Helgason, Hrefna S Johannsdottir, Anna Helgadottir, Hreinn Stefansson, Solveig Gretarsdottir, Thorunn Rafnar, Ina S Almdahl, Anne Brækhus, Tormod Fladby, Geir Selbæk, Farhad Hosseinpanah, Fereidoun Azizi, Jung Min Koh, Nelson L S Tang, Maryams Danesphour, Jose I Mayordomo, Corrine Welt, Peter S Braund, Nilesh J Samani, Lambertus A Kiemeney, L Stefan Lohmander, Claus Christiansen, Ole A Andreassen, arcOGEN consortium, Olafur Magnusson, Gisli Masson, Augustine Kong, Ingileif Jonsdottir, Daniel Gudbjartsson, Patrick Sulem, Helgi Jonsson, John Loughlin, Thorvaldur Ingvarsson, Unnur Thorsteinsdottir & Kari Stefansson doi:10.1038/ng0817-1286b
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