Nature Genetics Publishes the very highest quality research in genetics. http://www.nature.com/ng/current_issue/ Nature Publishing Group en © Nature Publishing Group Nature Genetics 1061-4036 1546-1718 © Nature Publishing Group permissions@nature.com Nature Genetics http://www.nature.com/includes/rj_globnavimages/ng_logo.gif http://www.nature.com/ng/ Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57 http://dx.doi.org/10.1038/ng.187 Deborah Mackay and colleagues identify mutations in ZFP57, encoding a zinc-finger transcription factor, in families with transient neonatal diabetes and additional clinical features. Affected individuals have a variable pattern of DNA hypomethylation at multiple imprinted loci. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57

Nature Genetics. doi:10.1038/ng.187

Authors: Deborah J G Mackay, Jonathan L A Callaway, Sophie M Marks, Helen E White, Carlo L Acerini, Susanne E Boonen, Pinar Dayanikli, Helen V Firth, Judith A Goodship, Andreas P Haemers, Johanne M D Hahnemann, Olga Kordonouri, Ahmed F Masoud, Elsebet Oestergaard, John Storr, Sian Ellard, Andrew T Hattersley, David O Robinson & I Karen Temple

We have previously described individuals presenting with transient neonatal diabetes and showing a variable pattern of DNA hypomethylation at imprinted loci throughout the genome. We now report mutations in ZFP57, which encodes a zinc-finger transcription factor expressed in early development, in seven pedigrees with a shared pattern of mosaic hypomethylation and a conserved range of clinical features. This is the first description of a heritable global imprinting disorder that is compatible with life.

]]> Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57 Deborah J G Mackay Jonathan L A Callaway Sophie M Marks Helen E White Carlo L Acerini Susanne E Boonen Pinar Dayanikli Helen V Firth Judith A Goodship Andreas P Haemers Johanne M D Hahnemann Olga Kordonouri Ahmed F Masoud Elsebet Oestergaard John Storr Sian Ellard Andrew T Hattersley David O Robinson I Karen Temple doi:10.1038/ng.187 Nature Genetics 2008-07-11 Nature Genetics 2008-07-11 Brief Communication Common nonsynonymous variants in PCSK1 confer risk of obesity http://dx.doi.org/10.1038/ng.177 Philippe Froguel and colleagues report that common nonsynonymous variants in PCSK1, encoding a prohormone convertase, confer risk of obesity in individuals of European ancestry. Common nonsynonymous variants in PCSK1 confer risk of obesity

Nature Genetics. doi:10.1038/ng.177

Authors: Michael Benzinou, John W M Creemers, Helene Choquet, Stephane Lobbens, Christian Dina, Emmanuelle Durand, Audrey Guerardel, Philippe Boutin, Beatrice Jouret, Barbara Heude, Beverley Balkau, Jean Tichet, Michel Marre, Natascha Potoczna, Fritz Horber, Catherine Le Stunff, Sebastien Czernichow, Annelli Sandbaek, Torsten Lauritzen, Knut Borch-Johnsen, Gitte Andersen, Wieland Kiess, Antje Körner, Peter Kovacs, Peter Jacobson, Lena M S Carlsson, Andrew J Walley, Torben Jørgensen, Torben Hansen, Oluf Pedersen, David Meyre & Philippe Froguel

]]> Common nonsynonymous variants in PCSK1 confer risk of obesity Michael Benzinou John W M Creemers Helene Choquet Stephane Lobbens Christian Dina Emmanuelle Durand Audrey Guerardel Philippe Boutin Beatrice Jouret Barbara Heude Beverley Balkau Jean Tichet Michel Marre Natascha Potoczna Fritz Horber Catherine Le Stunff Sebastien Czernichow Annelli Sandbaek Torsten Lauritzen Knut Borch-Johnsen Gitte Andersen Wieland Kiess Antje Körner Peter Kovacs Peter Jacobson Lena M S Carlsson Andrew J Walley Torben Jørgensen Torben Hansen Oluf Pedersen David Meyre Philippe Froguel doi:10.1038/ng.177 Nature Genetics 2008-07-06 Nature Genetics 2008-07-06 Brief Communication Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension http://dx.doi.org/10.1038/ng.164 Theodore Kurtz and colleagues report that Cd36 expression in the kidney underlies a quantitative trait locus for essential hypertension in the rat. Cd36 affects levels of cyclic GMP, a downstream effector of nitric oxide signaling, consistent with published data that reduced nitric oxide activity in the kidney is associated with hypertension. Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension

Nature Genetics. doi:10.1038/ng.164

Authors: Michal Pravenec, Paul C Churchill, Monique C Churchill, Ondrej Viklicky, Ludmila Kazdova, Timothy J Aitman, Enrico Petretto, Norbert Hubner, Caroline A Wallace, Heike Zimdahl, Vaclav Zidek, Vladimir Landa, Joseph Dunbar, Anil Bidani, Karen Griffin, Nathan Qi, Martina Maxova, Vladimir Kren, Petr Mlejnek, Jiaming Wang & Theodore W Kurtz

To identify renally expressed genes that influence risk for hypertension, we integrated expression quantitative trait locus (QTL) analysis of the kidney with genome-wide correlation analysis of renal expression profiles and blood pressure in recombinant inbred strains derived from the spontaneously hypertensive rat (SHR). This strategy, together with renal transplantation studies in SHR progenitor, transgenic and congenic strains, identified deficient renal expression of Cd36 encoding fatty acid translocase as a genetically determined risk factor for spontaneous hypertension.

]]> Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension Michal Pravenec Paul C Churchill Monique C Churchill Ondrej Viklicky Ludmila Kazdova Timothy J Aitman Enrico Petretto Norbert Hubner Caroline A Wallace Heike Zimdahl Vaclav Zidek Vladimir Landa Joseph Dunbar Anil Bidani Karen Griffin Nathan Qi Martina Maxova Vladimir Kren Petr Mlejnek Jiaming Wang Theodore W Kurtz doi:10.1038/ng.164 Nature Genetics 2008-06-29 Nature Genetics 2008-06-29 Brief Communication Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease http://dx.doi.org/10.1038/ng.175 Mark Daly and colleagues present results of a combined analysis of data from three recent genome-wide association studies for Crohn's disease, followed by replication in a large independent sample collection. Their results confirm 11 previously reported risk loci and provide genome-wide significant evidence for 21 new loci associated with the disease. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

Nature Genetics. doi:10.1038/ng.175

Authors: Jeffrey C Barrett, Sarah Hansoul, Dan L Nicolae, Judy H Cho, Richard H Duerr, John D Rioux, Steven R Brant, Mark S Silverberg, Kent D Taylor, M Michael Barmada, Alain Bitton, Themistocles Dassopoulos, Lisa Wu Datta, Todd Green, Anne M Griffiths, Emily O Kistner, Michael T Murtha, Miguel D Regueiro, Jerome I Rotter, L Philip Schumm, A Hillary Steinhart, Stephan R Targan, Ramnik J Xavier, Cécile Libioulle, Cynthia Sandor, Mark Lathrop, Jacques Belaiche, Olivier Dewit, Ivo Gut, Simon Heath, Debby Laukens, Myriam Mni, Paul Rutgeerts, André Van Gossum, Diana Zelenika, Denis Franchimont, Jean-Pierre Hugot, Martine de Vos, Severine Vermeire, Edouard Louis, Lon R Cardon, Carl A Anderson, Hazel Drummond, Elaine Nimmo, Tariq Ahmad, Natalie J Prescott, Clive M Onnie, Sheila A Fisher, Jonathan Marchini, Jilur Ghori, Suzannah Bumpstead, Rhian Gwilliam, Mark Tremelling, Panos Deloukas, John Mansfield, Derek Jewell, Jack Satsangi, Christopher G Mathew, Miles Parkes, Michel Georges & Mark J Daly

]]> Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease Jeffrey C Barrett Sarah Hansoul Dan L Nicolae Judy H Cho Richard H Duerr John D Rioux Steven R Brant Mark S Silverberg Kent D Taylor M Michael Barmada Alain Bitton Themistocles Dassopoulos Lisa Wu Datta Todd Green Anne M Griffiths Emily O Kistner Michael T Murtha Miguel D Regueiro Jerome I Rotter L Philip Schumm A Hillary Steinhart Stephan R Targan Ramnik J Xavier Cécile Libioulle Cynthia Sandor Mark Lathrop Jacques Belaiche Olivier Dewit Ivo Gut Simon Heath Debby Laukens Myriam Mni Paul Rutgeerts André Van Gossum Diana Zelenika Denis Franchimont Jean-Pierre Hugot Martine de Vos Severine Vermeire Edouard Louis Lon R Cardon Carl A Anderson Hazel Drummond Elaine Nimmo Tariq Ahmad Natalie J Prescott Clive M Onnie Sheila A Fisher Jonathan Marchini Jilur Ghori Suzannah Bumpstead Rhian Gwilliam Mark Tremelling Panos Deloukas John Mansfield Derek Jewell Jack Satsangi Christopher G Mathew Miles Parkes Michel Georges Mark J Daly doi:10.1038/ng.175 Nature Genetics 2008-06-29 Nature Genetics 2008-06-29 Article Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians http://dx.doi.org/10.1038/ng.168 Wolf Reik and Ian Dunham and colleagues cloned and sequenced the complete IGF2-H19 locus in tammar wallaby, a marsupial. Functional analyses revealed conservation of imprinting mechanisms, including germline DNA methylation, between marsupials and eutherians. Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians

Nature Genetics. doi:10.1038/ng.168

Authors: Guillaume Smits, Andrew J Mungall, Sam Griffiths-Jones, Paul Smith, Delphine Beury, Lucy Matthews, Jane Rogers, Andrew J Pask, Geoff Shaw, John L VandeBerg, John R McCarrey, Marilyn B Renfree, Wolf Reik & Ian Dunham

]]> Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians Guillaume Smits Andrew J Mungall Sam Griffiths-Jones Paul Smith Delphine Beury Lucy Matthews Jane Rogers Andrew J Pask Geoff Shaw John L VandeBerg John R McCarrey Marilyn B Renfree Wolf Reik Ian Dunham doi:10.1038/ng.168 Nature Genetics 2008-06-29 Nature Genetics 2008-06-29 Article Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis http://dx.doi.org/10.1038/ng.176 Shiro Ikegawa and colleagues identify a variant in a previously unknown gene, DVWA, that is associated with susceptibility to knee osteoarthritis. DVWA contains von Willebrand factor domains and is expressed specifically in cartilage. Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis

Nature Genetics. doi:10.1038/ng.176

Authors: Yoshinari Miyamoto, Dongquan Shi, Masahiro Nakajima, Kouichi Ozaki, Akihiro Sudo, Akihiro Kotani, Atsumasa Uchida, Toshihiro Tanaka, Naoshi Fukui, Tatsuhiko Tsunoda, Atsushi Takahashi, Yusuke Nakamura, Qing Jiang & Shiro Ikegawa

Susceptibility to osteoarthritis, the most common human arthritis, is known to be influenced by genetic factors. Through a genome-wide association study using ∼100,000 SNPs, we have identified a previously unknown gene on chromosome 3p24.3, DVWA, which is associated with susceptibility to knee osteoarthritis. Expressed specifically in cartilage, DVWA encodes a 276-amino-acid protein with two regions corresponding to the von Willebrand factor type A domain (VWA domain). Several DVWA SNPs are significantly associated with knee osteoarthritis in two independent Japanese case-control cohorts. This association was replicated in a Japanese population cohort and a Han Chinese case-control cohort (combined P = 7.3 × 10−11). DVWA protein binds to β-tubulin, and the binding is influenced by two highly associated missense SNPs (rs11718863 and rs7639618) located in the VWA domain. The Tyr169-Cys260 isoform of DVWA, which is overrepresented in knee osteoarthritis, showed weaker interaction. Our findings reveal a new paradigm for study of osteoarthritis etiology and pathogenesis.

]]> Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis Yoshinari Miyamoto Dongquan Shi Masahiro Nakajima Kouichi Ozaki Akihiro Sudo Akihiro Kotani Atsumasa Uchida Toshihiro Tanaka Naoshi Fukui Tatsuhiko Tsunoda Atsushi Takahashi Yusuke Nakamura Qing Jiang Shiro Ikegawa doi:10.1038/ng.176 Nature Genetics 2008-07-11 Nature Genetics 2008-07-11 Letter Critical function of Prdm14 for the establishment of the germ cell lineage in mice http://dx.doi.org/10.1038/ng.186 Mitinori Saitou and colleagues report that Prdm14, which encodes a transcription factor expressed exclusively in the germ cell lineage, is essential for re-acquisition of pluripotency and epigenetic reprogramming of primordial germ cells. Critical function of Prdm14 for the establishment of the germ cell lineage in mice

Nature Genetics. doi:10.1038/ng.186

Authors: Masashi Yamaji, Yoshiyuki Seki, Kazuki Kurimoto, Yukihiro Yabuta, Mihoko Yuasa, Mayo Shigeta, Kaori Yamanaka, Yasuhide Ohinata & Mitinori Saitou

Specification of germ cell fate is fundamental in development and heredity. Recent evidence indicates that in mice, specification of primordial germ cells (PGCs), the common source of both oocytes and spermatozoa, occurs through the integration of three key events: repression of the somatic program, reacquisition of potential pluripotency and ensuing genome-wide epigenetic reprogramming. Here we provide genetic evidence that Prdm14, a PR domain–containing transcriptional regulator with exclusive expression in the germ cell lineage and pluripotent cell lines, is critical in two of these events, the reacquisition of potential pluripotency and successful epigenetic reprogramming. In Prdm14 mutants, the failure of these two events manifests even in the presence of Prdm1 (also known as Blimp1), a key transcriptional regulator for PGC specification. Our combined evidence demonstrates that Prdm14 defines a previously unknown genetic pathway, initiating independently from Prdm1, for ensuring the launching of the mammalian germ cell lineage.

]]> Critical function of Prdm14 for the establishment of the germ cell lineage in mice Masashi Yamaji Yoshiyuki Seki Kazuki Kurimoto Yukihiro Yabuta Mihoko Yuasa Mayo Shigeta Kaori Yamanaka Yasuhide Ohinata Mitinori Saitou doi:10.1038/ng.186 Nature Genetics 2008-07-11 Nature Genetics 2008-07-11 Letter Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease http://dx.doi.org/10.1038/ng.179 Helen McNeill and colleagues show that loss of Fat4, a homolog of the Drosophila planar cell polarity protein Fat, disrupts oriented cell division, leading to a failure of tubule elongation and cystic kidney disease in mice. The findings suggest that loss of planar cell polarity may underlie some forms of cystic kidney disease in humans. Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease

Nature Genetics. doi:10.1038/ng.179

Authors: Sakura Saburi, Ian Hester, Evelyne Fischer, Marco Pontoglio, Vera Eremina, Manfred Gessler, Sue E Quaggin, Robert Harrison, Richard Mount & Helen McNeill

Tissue organization in Drosophila is regulated by the core planar cell polarity (PCP) proteins Frizzled, Dishevelled, Prickle, Van Gogh and Flamingo. Core PCP proteins are conserved in mammals and function in mammalian tissue organization. Recent studies have identified another group of Drosophila PCP proteins, consisting of the protocadherins Fat and Dachsous (Ds) and the transmembrane protein Four-jointed (Fj). In Drosophila, Fat represses fj transcription, and Ds represses Fat activity in PCP. Here we show that Fat4 is an essential gene that has a key role in vertebrate PCP. Loss of Fat4 disrupts oriented cell divisions and tubule elongation during kidney development, leading to cystic kidney disease. Fat4 genetically interacts with the PCP genes Vangl2 and Fjx1 in cyst formation. In addition, Fat4 represses Fjx1 expression, indicating that Fat signaling is conserved. Together, these data suggest that Fat4 regulates vertebrate PCP and that loss of PCP signaling may underlie some cystic diseases in humans.

]]> Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease Sakura Saburi Ian Hester Evelyne Fischer Marco Pontoglio Vera Eremina Manfred Gessler Sue E Quaggin Robert Harrison Richard Mount Helen McNeill doi:10.1038/ng.179 Nature Genetics 2008-07-06 Nature Genetics 2008-07-06 Letter Deletion in a gene associated with grain size increased yields during rice domestication http://dx.doi.org/10.1038/ng.169 Takeshi Izawa and colleagues report the cloning of a gene underlying a rice quantitative trait locus influencing grain width. A deletion in qSW5 increases yield of rice grains, and the authors show that this mutation has likely been selected for during the domestication of rice. Deletion in a gene associated with grain size increased yields during rice domestication

Nature Genetics. doi:10.1038/ng.169

Authors: Ayahiko Shomura, Takeshi Izawa, Kaworu Ebana, Takeshi Ebitani, Hiromi Kanegae, Saeko Konishi & Masahiro Yano

The domestication of crops involves a complex process of selection in plant evolution and is associated with changes in the DNA regulating agronomically important traits. Here we report the cloning of a newly identified QTL, qSW5 (QTL for seed width on chromosome 5), involved in the determination of grain width in rice. Through fine mapping, complementation testing and association analysis, we found that a deletion in qSW5 resulted in a significant increase in sink size owing to an increase in cell number in the outer glume of the rice flower; this trait might have been selected by ancient humans to increase yield of rice grains. In addition, we mapped two other defective functional nucleotide polymorphisms of rice domestication-related genes with genome-wide RFLP polymorphisms of various rice landraces. These analyses show that the qSW5 deletion had an important historical role in artificial selection, propagation of cultivation and natural crossings in rice domestication, and shed light on how the rice genome was domesticated.

]]> Deletion in a gene associated with grain size increased yields during rice domestication Ayahiko Shomura Takeshi Izawa Kaworu Ebana Takeshi Ebitani Hiromi Kanegae Saeko Konishi Masahiro Yano doi:10.1038/ng.169 Nature Genetics 2008-07-06 Nature Genetics 2008-07-06 Letter Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia http://dx.doi.org/10.1038/ng.166 Daniel Cohn and colleagues identify mutations in the gene encoding the calcium-permeable cation channel TRPV4 in families with autosomal dominant brachyolmia. Functional studies show that the mutations result in gain-of-function of channel activation. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia

Nature Genetics. doi:10.1038/ng.166

Authors: Matthew J Rock, Jean Prenen, Vincent A Funari, Tara L Funari, Barry Merriman, Stanley F Nelson, Ralph S Lachman, William R Wilcox, Soraya Reyno, Roberto Quadrelli, Alicia Vaglio, Grzegorz Owsianik, Annelies Janssens, Thomas Voets, Shiro Ikegawa, Toshiro Nagai, David L Rimoin, Bernd Nilius & Daniel H Cohn

The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature. Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1–12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4α-phorbol 12,13-didecanoate (4αPDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.

]]> Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia Matthew J Rock Jean Prenen Vincent A Funari Tara L Funari Barry Merriman Stanley F Nelson Ralph S Lachman William R Wilcox Soraya Reyno Roberto Quadrelli Alicia Vaglio Grzegorz Owsianik Annelies Janssens Thomas Voets Shiro Ikegawa Toshiro Nagai David L Rimoin Bernd Nilius Daniel H Cohn doi:10.1038/ng.166 Nature Genetics 2008-06-29 Nature Genetics 2008-06-29 Letter