Cis-Acting Regulation of Brain-Specific ANK3 Gene Expression by a Genetic Variant Associated with Bipolar Disorder
E H Rueckert,Douglas Barker,Douglas M. Ruderfer,Sarah E. Bergen,Sarah E. Bergen,Colm O'Dushlaine,Catherine J. Luce,Steven D. Sheridan,Kraig M. Theriault,Kimberly Chambert,Jennifer L. Moran,Shaun Purcell,Jon M. Madison,Stephen J. Haggarty,Pamela Sklar +14 more
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TLDR
Differential regulation of distinct ANK3 transcription start sites and coupling of specific 5′ ends with 3′ mRNA splicing events in postmortem human brain and human stem cell-derived neural progenitors and neurons are detected.Abstract:
Several genome-wide association studies (GWAS) for bipolar disorder (BD) have found a strong association of the Ankyrin3 (ANK3) gene. This association spans numerous linked single nucleotide polymorphisms (SNPs) in a ~250 kb genomic region overlapping ANK3. The associated region encompasses predicted regulatory elements as well as two of six validated alternative first exons, which encode distinct protein domains at the N-terminus of the protein also known as ankyrin-G (AnkG). Using RNA Ligase-Mediated Rapid Amplification of cDNA Ends (RLM-RACE) to identify novel transcripts in conjunction with a highly sensitive, exon-specific multiplexed mRNA expression assay, we detected differential regulation of distinct ANK3 transcription start sites (TSSs) and coupling of specific 5’ ends with 3’ mRNA splicing events in post-mortem human brain and human stem cell-derived neural progenitors and neurons. Furthermore, allelic variation at the BD–associated SNP rs1938526 correlated with a significant difference in cerebellar expression of a brain-specific ANK3 transcript. These findings suggest a brain-specific cis-regulatory transcriptional effect of ANK3 may be relevant to BD pathophysiology.read more
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Journal ArticleDOI
Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders
Zafar Iqbal,Geert Vandeweyer,Monique van der Voet,Ali Muhammad Waryah,Ali Muhammad Waryah,Ali Muhammad Waryah,Muhammad Yasir Zahoor,Muhammad Yasir Zahoor,Judith A. Besseling,Laura Tomas Roca,Anneke T. Vulto-van Silfhout,Bonnie Nijhof,Jamie M. Kramer,Nathalie Van der Aa,Muhammad Ansar,Muhammad Ansar,Hilde Peeters,Céline Helsmoortel,Christian Gilissen,Lisenka E.L.M. Vissers,Joris A. Veltman,Arjan P.M. de Brouwer,R. Frank Kooy,Sheikh Riazuddin,Sheikh Riazuddin,Annette Schenck,Hans van Bokhoven,Liesbeth Rooms +27 more
TL;DR: Inactivating mutations in the Ankyrin 3 (ANK3) gene in patients with severe cognitive deficits support the suggested association of ANK3 with various neuropsychiatric disorders and illustrate the genetic and molecular relation between a wide range of neurodevelopmental disorders.
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Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder.
Sabine Bavamian,Nikolaos Mellios,Jasmin Lalonde,Daniel M. Fass,Daniel M. Fass,Jennifer P. Wang,Steven D. Sheridan,Jon M. Madison,Fen Zhou,Fen Zhou,E H Rueckert,E H Rueckert,Doug Barker,Roy H. Perlis,Mriganka Sur,Stephen J. Haggarty +15 more
TL;DR: It is proposed that miR-34a serves as a critical link between multiple etiological factors for BD and its pathogenesis through the regulation of a molecular network essential for neuronal development and synaptogenesis.
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The genetics of bipolar disorder.
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Comprehensive comparative analysis of 5′-end RNA-sequencing methods
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TL;DR: It is found that the ‘cap analysis of gene expression’ (CAGE) method performed best for mRNA and that most of its unannotated peaks were supported by evidence from other genomic methods.
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Glial ankyrins facilitate paranodal axoglial junction assembly
Kae-Jiun Chang,Daniel R. Zollinger,Keiichiro Susuki,Diane L. Sherman,Michael A. Makara,Peter J. Brophy,Edward C. Cooper,Vann Bennett,Peter J. Mohler,Matthew N. Rasband +9 more
TL;DR: Glial ankyrins function as major scaffolds that facilitate early and efficient paranodal junction assembly in the developing CNS.
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Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4
Pamela Sklar,Pamela Sklar,Stephan Ripke,Stephan Ripke,Laura J. Scott,Ole A. Andreassen,Sven Cichon,Nicholas John Craddock,Howard J. Edenberg,John I. Nurnberger,Marcella Rietschel,Douglas Blackwood,Aiden Corvin,Matthew Flickinger,Weihua Guan,Morten Mattingsdal,Andrew McQuillin,Phoenix Kwan,Thomas F. Wienker,Mark J. Daly,Mark J. Daly,Frank Dudbridge,Peter Holmans,Danyu Lin,Margit Burmeister,Tiffany A. Greenwood,Marian L. Hamshere,Pierandrea Muglia,Erin N. Smith,Peter P. Zandi,Caroline M. Nievergelt,Rebecca McKinney,Paul D. Shilling,Nicholas J. Schork,Cinnamon S. Bloss,Tatiana Foroud,Daniel L. Koller,Elliot S. Gershon,Chunyu Liu,Judith A. Badner,William A. Scheftner,William Lawson,Evaristus A. Nwulia,Maria Hipolito,William Coryell,John P. Rice,William Byerley,Francis J. McMahon,Thomas G. Schulze,Thomas G. Schulze,Thomas G. Schulze,Wade H. Berrettini,Falk W. Lohoff,James B. Potash,Pamela B. Mahon,Melvin G. McInnis,Sebastian Zöllner,Peng Zhang,David Craig,Szabocls Szelinger,Thomas B. Barrett,René Breuer,Sandra Meier,Jana Strohmaier,Stephanie H. Witt,Federica Tozzi,Anne Farmer,Peter McGuffin,John Strauss,Wei Xu,James L. Kennedy,John B. Vincent,Keith Matthews,Richard O. Day,Manuel A. R. Ferreira,Manuel A. R. Ferreira,Manuel A. R. Ferreira,Colm O'Dushlaine,Colm O'Dushlaine,Roy H. Perlis,Roy H. Perlis,Soumya Raychaudhuri,Soumya Raychaudhuri,Douglas M. Ruderfer,Douglas M. Ruderfer,Phil Lee,Jordan W. Smoller,Jordan W. Smoller,Jun Li,Devin Absher,William E. Bunney,Jack D. Barchas,Alan F. Schatzberg,Edward G. Jones,Fan Meng,Robert C. Thompson,Stanley J. Watson,Richard M. Myers,Huda Akil,Michael Boehnke,Kim Chambert,Jennifer L. Moran,Edward M. Scolnick,Srdjan Djurovic,Ingrid Melle,Gunnar Morken,Michael Gill,Derek W. Morris,Emma M. Quinn,Thomas W. Mühleisen,Franziska Degenhardt,Manuel Mattheisen,Johannes Schumacher,Wolfgang Maier,Michael Steffens,Peter Propping,Markus M. Nöthen,Adebayo Anjorin,Nick Bass,Hugh Gurling,Radhika Kandaswamy,Jacob Lawrence,Kevin A. McGhee,Andrew M. McIntosh,Alan W. McLean,Walter J. Muir,Benjamin S. Pickard,Gerome Breen,Gerome Breen,David St Clair,Sian Caesar,Katherine Gordon-Smith,Katherine Gordon-Smith,Lisa Jones,Christine Fraser,Elaine K. Green,Detelina Grozeva,Ian Jones,George Kirov,Valentina Moskvina,Ivan Nikolov,Michael Conlon O'Donovan,Michael John Owen,David A. Collier,Amanda Elkin,Richard Williamson,Allan H. Young,Allan H. Young,I. Nicol Ferrier,Kari Stefansson,Hreinn Stefansson,Porgeir Porgeirsson,Stacy Steinberg,Omar Gustafsson,Sarah E. Bergen,Sarah E. Bergen,Vishwajit L. Nimgaonkar,Christina M. Hultman,Mikael Landén,Mikael Landén,Paul Lichtenstein,Patrick F. Sullivan,Martin Schalling,Urban Ösby,Lena Backlund,Louise Frisén,Niklas Långström,Stéphane Jamain,Marion Leboyer,Bruno Etain,Frank Bellivier,Hannes Petursson,Engilbert Sigurdsson,Bertram Müller-Mysok,Susanne Lucae,Markus J. Schwarz,Janice M. Fullerton,Janice M. Fullerton,Peter R. Schofield,Peter R. Schofield,Nicholas G. Martin,Grant W. Montgomery,Mark Lathrop,Hogni Oskarsson,Michael Bauer,Adam Wright,Philip B. Mitchell,Martin Hautzinger,Andreas Reif,John R. Kelsoe,Shaun Purcell,Shaun Purcell,Shaun Purcell +192 more
TL;DR: An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4, and a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals was identified.
Journal ArticleDOI
Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder
Manuel A. R. Ferreira,Michael Conlon O'Donovan,Yan A Meng,Ian Jones,Douglas M. Ruderfer,Lisa Jones,Jinbo Fan,George Kirov,Roy H. Perlis,Elaine K. Green,Jordan W. Smoller,Detelina Grozeva,Jennifer Stone,Ivan Nikolov,Kimberly Chambert,Marian L. Hamshere,Vishwajit L. Nimgaonkar,Valentina Moskvina,Michael E. Thase,Michael E. Thase,Sian Caesar,Gary S. Sachs,Jennifer Franklin,Katherine Gordon-Smith,Katherine Gordon-Smith,Kristin G. Ardlie,Stacey Gabriel,Christine Fraser,Brendan Blumenstiel,Matthew Defelice,Gerome Breen,Gerome Breen,Michael Gill,Derek W. Morris,Amanda Elkin,Walter J. Muir,Kevin A. McGhee,Richard Williamson,Donald J. MacIntyre,Alan W Maclean,David St Clair,Michelle Robinson,Margaret Van Beck,Ana C. Parente Pereira,Radhika Kandaswamy,Andrew McQuillin,David A. Collier,Nicholas Bass,Allan H. Young,Jacob Lawrence,I. Nicol Ferrier,Adebayo Anjorin,Anne Farmer,David Curtis,Edward M. Scolnick,Edward M. Scolnick,Peter McGuffin,Mark J. Daly,Aiden Corvin,Peter Holmans,Douglas Blackwood,Hugh Gurling,Michael John Owen,Shaun Purcell,Pamela Sklar,Nicholas John Craddock +65 more
TL;DR: The results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder and found further support for the previously reported CACNA1C.
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AnkyrinG. A new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier.
Genome-wide association study reveals two new risk loci for bipolar disorder
Thomas W. Mühleisen,Thomas W. Mühleisen,Markus Leber,Markus Leber,Thomas G. Schulze,Jana Strohmaier,Franziska Degenhardt,Jens Treutlein,Manuel Mattheisen,Manuel Mattheisen,Andreas J. Forstner,Johannes Schumacher,René Breuer,Sandra Meier,Stefan Herms,Stefan Herms,Per Hoffmann,André Lacour,Stephanie H. Witt,Andreas Reif,Bertram Müller-Myhsok,Bertram Müller-Myhsok,Susanne Lucae,Wolfgang Maier,M.P. Schwarz,Helmut Vedder,Jutta Kammerer-Ciernioch,Andrea Pfennig,Michael Bauer,Martin Hautzinger,Susanne Moebus,Lutz Priebe,Piotr M. Czerski,Joanna Hauser,Jolanta Lissowska,Neonila Szeszenia-Dabrowska,Paul Brennan,James McKay,Adam Wright,Adam Wright,Philip B. Mitchell,Philip B. Mitchell,Janice M. Fullerton,Janice M. Fullerton,Peter R. Schofield,Peter R. Schofield,Grant W. Montgomery,Sarah E. Medland,Scott D. Gordon,Nicholas G. Martin,Valery Krasnow,Alexander Chuchalin,Gulja Babadjanova,Galina Pantelejeva,Lilia I. Abramova,Alexander S. Tiganov,Alexey Polonikov,Elza Khusnutdinova,Martin Alda,Paul Grof,Guy A. Rouleau,Gustavo Turecki,Catherine Laprise,Fabio Rivas,Fermín Mayoral,Manolis Kogevinas,Maria Grigoroiu-Serbanescu,Peter Propping,Tim Becker,Tim Becker,Marcella Rietschel,Markus M. Nöthen,Sven Cichon +72 more