Volume 50 Issue 3, March 2018

Volume 50 Issue 3

Cape porcupine quills by Tony Cunningham (tonysartandnature.com)

Image credit: Tony Cunningham Cover Design: Erin Dewalt

Editorial

  • Editorial |

    The multiple standardized clinical measurements that make up one’s lifetime path through health and disease are essential information for yourself and your healthcare system. Aggregated into a population cohort study across a single-payer network, these data become an extraordinary tool for improving the efficiency of healthcare delivery and new discoveries in genomic medicine.

News & Views

  • News & Views |

    Maternal high-fat diet has a negative impact on fertility—including an apparent direct effect on early development. In this issue, a new study connects this phenotype to depletion of Stella protein in oocytes, demonstrating environmental regulation of a maternal-effect gene.

    • Harry G. Leitch
    •  & Petra Hajkova
  • News & Views |

    Alterations in craniofacial size and shape are apparent in many monogenic diseases and syndromes, but remarkably little is known about the genetics of face shape within healthy populations. This may be set to change following publication of a study that combines unsupervised hierarchical spectral clustering and canonical correlation analysis to help identify common genetic variants associated with craniofacial shape.

    • David M. Evans

Perspectives

  • Perspective |

    This Perspective describes different study designs for the genetic analyses of large-scale cohorts, using Dutch cohorts as primary examples, and discusses lessons learned as well as recommendations for future cohort studies.

    • Cisca Wijmenga
    •  & Alexandra Zhernakova

Brief Communications

  • Brief Communication |

    The clinical phenotype associated with BRD4 haploinsufficiency overlaps with Cornelia de Lange syndrome, which is often caused by mutations in NIPBL. The authors show that BRD4 and NIPBL physically interact and co-bind at super-enhancers.

    • Gabrielle Olley
    • , Morad Ansari
    • , Hemant Bengani
    • , Graeme R. Grimes
    • , James Rhodes
    • , Alex von Kriegsheim
    • , Ana Blatnik
    • , Fiona J. Stewart
    • , Emma Wakeling
    • , Nicola Carroll
    • , Alison Ross
    • , Soo-Mi Park
    • , Wendy A. Bickmore
    • , Madapura M. Pradeepa
    •  & David R. FitzPatrick

Letters

  • Letter |

    This study presents a map of sequence constraint in humans based on 11,257 whole-genome sequences and 16,384 heptamers. The map identifies regulatory elements among the most constrained regions of the genome and will aid interpretation of noncoding variants.

    • Julia di Iulio
    • , Istvan Bartha
    • , Emily H. M. Wong
    • , Hung-Chun Yu
    • , Victor Lavrenko
    • , Dongchan Yang
    • , Inkyung Jung
    • , Michael A. Hicks
    • , Naisha Shah
    • , Ewen F. Kirkness
    • , Martin M. Fabani
    • , William H. Biggs
    • , Bing Ren
    • , J. Craig Venter
    •  & Amalio Telenti
  • Letter |

    Exome-wide analyses identify low-frequency coding variants associated with esophageal squamous cell carcinoma. One of the risk variants, in CYP26B1, is associated with enhanced enzymatic activity and lower levels of all-trans retinoic acid in serum.

    • Jiang Chang
    • , Rong Zhong
    • , Jianbo Tian
    • , Jiaoyuan Li
    • , Kan Zhai
    • , Juntao Ke
    • , Jiao Lou
    • , Wei Chen
    • , Beibei Zhu
    • , Na Shen
    • , Yi Zhang
    • , Ying Zhu
    • , Yajie Gong
    • , Yang Yang
    • , Danyi Zou
    • , Xiating Peng
    • , Zhi Zhang
    • , Xuemei Zhang
    • , Kun Huang
    • , Tangchun Wu
    • , Chen Wu
    • , Xiaoping Miao
    •  & Dongxin Lin
  • Letter |

    Biallelic loss-of-function mutations in TGFB1 are reported in three individuals with severe infantile inflammatory bowel disease and neurodevelopmental delay. These findings highlight a critical role for TGF-β1 in human intestinal homeostasis and central nervous system development.

    • Daniel Kotlarz
    • , Benjamin Marquardt
    • , Tuva Barøy
    • , Way S. Lee
    • , Liza Konnikova
    • , Sebastian Hollizeck
    • , Thomas Magg
    • , Anna S. Lehle
    • , Christoph Walz
    • , Ingo Borggraefe
    • , Fabian Hauck
    • , Philip Bufler
    • , Raffaele Conca
    • , Sarah M. Wall
    • , Eva M. Schumacher
    • , Doriana Misceo
    • , Eirik Frengen
    • , Beint S. Bentsen
    • , Holm H. Uhlig
    • , Karl-Peter Hopfner
    • , Aleixo M. Muise
    • , Scott B. Snapper
    • , Petter Strømme
    •  & Christoph Klein
  • Letter |

    Whole-exome sequencing identifies mutations in CLCN2 in individuals with familial hyperaldosteronism type II or early-onset primary aldosteronism. These gain-of-function mutations cause chloride channel opening and glomerulosa cell depolarization, showing a role for anion channels in aldosterone production.

    • Ute I. Scholl
    • , Gabriel Stölting
    • , Julia Schewe
    • , Anne Thiel
    • , Hua Tan
    • , Carol Nelson-Williams
    • , Alfred A. Vichot
    • , Sheng Chih Jin
    • , Erin Loring
    • , Verena Untiet
    • , Taekyeong Yoo
    • , Jungmin Choi
    • , Shengxin Xu
    • , Aihua Wu
    • , Marieluise Kirchner
    • , Philipp Mertins
    • , Lars C. Rump
    • , Ali Mirza Onder
    • , Cory Gamble
    • , Daniel McKenney
    • , Robert W. Lash
    • , Deborah P. Jones
    • , Gary Chune
    • , Priscila Gagliardi
    • , Murim Choi
    • , Richard Gordon
    • , Michael Stowasser
    • , Christoph Fahlke
    •  & Richard P. Lifton
  • Letter |

    A gain-of-function mutation in the CLCN2 chloride channel gene (encoding ClC-2) causes primary aldosteronism. The mutation abolishes voltage-dependent gating of ClC-2, highlighting a role for chloride conduction in regulating aldosterone biosynthesis.

    • Fabio L. Fernandes-Rosa
    • , Georgios Daniil
    • , Ian J. Orozco
    • , Corinna Göppner
    • , Rami El Zein
    • , Vandana Jain
    • , Sheerazed Boulkroun
    • , Xavier Jeunemaitre
    • , Laurence Amar
    • , Hervé Lefebvre
    • , Thomas Schwarzmayr
    • , Tim M. Strom
    • , Thomas J. Jentsch
    •  & Maria-Christina Zennaro
  • Letter |

    Meta-analysis of data from 58,265 cattle shows that the genetic architecture underlying stature is similar to that in humans, where many genomic regions individually explain only a small amount of phenotypic variance.

    • Aniek C. Bouwman
    • , Hans D. Daetwyler
    • , Amanda J. Chamberlain
    • , Carla Hurtado Ponce
    • , Mehdi Sargolzaei
    • , Flavio S. Schenkel
    • , Goutam Sahana
    • , Armelle Govignon-Gion
    • , Simon Boitard
    • , Marlies Dolezal
    • , Hubert Pausch
    • , Rasmus F. Brøndum
    • , Phil J. Bowman
    • , Bo Thomsen
    • , Bernt Guldbrandtsen
    • , Mogens S. Lund
    • , Bertrand Servin
    • , Dorian J. Garrick
    • , James Reecy
    • , Johanna Vilkki
    • , Alessandro Bagnato
    • , Min Wang
    • , Jesse L. Hoff
    • , Robert D. Schnabel
    • , Jeremy F. Taylor
    • , Anna A. E. Vinkhuyzen
    • , Frank Panitz
    • , Christian Bendixen
    • , Lars-Erik Holm
    • , Birgit Gredler
    • , Chris Hozé
    • , Mekki Boussaha
    • , Marie-Pierre Sanchez
    • , Dominique Rocha
    • , Aurelien Capitan
    • , Thierry Tribout
    • , Anne Barbat
    • , Pascal Croiseau
    • , Cord Drögemüller
    • , Vidhya Jagannathan
    • , Christy Vander Jagt
    • , John J. Crowley
    • , Anna Bieber
    • , Deirdre C. Purfield
    • , Donagh P. Berry
    • , Reiner Emmerling
    • , Kay-Uwe Götz
    • , Mirjam Frischknecht
    • , Ingolf Russ
    • , Johann Sölkner
    • , Curtis P. Van Tassell
    • , Ruedi Fries
    • , Paul Stothard
    • , Roel F. Veerkamp
    • , Didier Boichard
    • , Mike E. Goddard
    •  & Ben J. Hayes
  • Letter |

    The authors report map-based cloning of the wheat Stb6 gene, which encodes a conserved wall-associated receptor kinase (WAK)-like protein. Stb6 confers gene-for-gene disease resistance to fungal pathogen Zymoseptoria tritici by recognition of a matching pathogen effector.

    • Cyrille Saintenac
    • , Wing-Sham Lee
    • , Florence Cambon
    • , Jason J. Rudd
    • , Robert C. King
    • , William Marande
    • , Stephen J. Powers
    • , Hélène Bergès
    • , Andy L. Phillips
    • , Cristobal Uauy
    • , Kim E. Hammond-Kosack
    • , Thierry Langin
    •  & Kostya Kanyuka
  • Letter |

    Identification of AvrStb6, the fungal avirulence effector that triggers Stb6-mediated resistance in wheat, here demonstrates that neither host resistance nor fungicide treatment suppresses fungal sexual reproduction, thus unveiling implications of fungal sex in plant disease control.

    • Gerrit H. J. Kema
    • , Amir Mirzadi Gohari
    • , Lamia Aouini
    • , Hesham A. Y. Gibriel
    • , Sarah B. Ware
    • , Frank van den Bosch
    • , Robbie Manning-Smith
    • , Vasthi Alonso-Chavez
    • , Joe Helps
    • , Sarrah Ben M’Barek
    • , Rahim Mehrabi
    • , Caucasella Diaz-Trujillo
    • , Elham Zamani
    • , Henk J. Schouten
    • , Theo A. J. van der Lee
    • , Cees Waalwijk
    • , Maarten A. de Waard
    • , Pierre J. G. M. de Wit
    • , Els C. P. Verstappen
    • , Bart P. H. J. Thomma
    • , Harold J. G. Meijer
    •  & Michael F. Seidl

Articles

  • Article |

    A new GWAS of schizophrenia (11,260 cases and 24,542 controls) and meta-analysis identifies 50 new associated loci and 145 loci in total. The common variant association signal is highly enriched in mutation-intolerant genes and in regions under strong background selection.

    • Antonio F. Pardiñas
    • , Peter Holmans
    • , Andrew J. Pocklington
    • , Valentina Escott-Price
    • , Stephan Ripke
    • , Noa Carrera
    • , Sophie E. Legge
    • , Sophie Bishop
    • , Darren Cameron
    • , Marian L. Hamshere
    • , Jun Han
    • , Leon Hubbard
    • , Amy Lynham
    • , Kiran Mantripragada
    • , Elliott Rees
    • , James H. MacCabe
    • , Steven A. McCarroll
    • , Bernhard T. Baune
    • , Gerome Breen
    • , Enda M. Byrne
    • , Udo Dannlowski
    • , Thalia C. Eley
    • , Caroline Hayward
    • , Nicholas G. Martin
    • , Andrew M. McIntosh
    • , Robert Plomin
    • , David J. Porteous
    • , Naomi R. Wray
    • , Armando Caballero
    • , Daniel H. Geschwind
    • , Laura M. Huckins
    • , Douglas M. Ruderfer
    • , Enrique Santiago
    • , Pamela Sklar
    • , Eli A. Stahl
    • , Hyejung Won
    • , Esben Agerbo
    • , Thomas D. Als
    • , Ole A. Andreassen
    • , Marie Bækvad-Hansen
    • , Preben Bo Mortensen
    • , Carsten Bøcker Pedersen
    • , Anders D. Børglum
    • , Jonas Bybjerg-Grauholm
    • , Srdjan Djurovic
    • , Naser Durmishi
    • , Marianne Giørtz Pedersen
    • , Vera Golimbet
    • , Jakob Grove
    • , David M. Hougaard
    • , Manuel Mattheisen
    • , Espen Molden
    • , Ole Mors
    • , Merete Nordentoft
    • , Milica Pejovic-Milovancevic
    • , Engilbert Sigurdsson
    • , Teimuraz Silagadze
    • , Christine Søholm Hansen
    • , Kari Stefansson
    • , Hreinn Stefansson
    • , Stacy Steinberg
    • , Sarah Tosato
    • , Thomas Werge
    • , Denise Harold
    • , Rebecca Sims
    • , Amy Gerrish
    • , Jade Chapman
    • , Valentina Escott-Price
    • , Richard Abraham
    • , Paul Hollingworth
    • , Jaspreet Pahwa
    • , Nicola Denning
    • , Charlene Thomas
    • , Sarah Taylor
    • , John Powell
    • , Petroula Proitsi
    • , Michelle Lupton
    • , Simon Lovestone
    • , Peter Passmore
    • , David Craig
    • , Bernadette McGuinness
    • , Janet Johnston
    • , Stephen Todd
    • , Wolfgang Maier
    • , Frank Jessen
    • , Reiner Heun
    • , Britta Schurmann
    • , Alfredo Ramirez
    • , Tim Becker
    • , Christine Herold
    • , André Lacour
    • , Dmitriy Drichel
    • , Markus Nothen
    • , Alison Goate
    • , Carlos Cruchaga
    • , Petra Nowotny
    • , John C. Morris
    • , Kevin Mayo
    • , Peter Holmans
    • , Michael O’Donovan
    • , Michael Owen
    • , Julie Williams
    • , Evanthia Achilla
    • , Esben Agerbo
    • , Cathy L. Barr
    • , Theresa Wimberly Böttger
    • , Gerome Breen
    • , Dan Cohen
    • , David A. Collier
    • , Sarah Curran
    • , Emma Dempster
    • , Danai Dima
    • , Ramon Sabes-Figuera
    • , Robert J. Flanagan
    • , Sophia Frangou
    • , Josef Frank
    • , Christiane Gasse
    • , Fiona Gaughran
    • , Ina Giegling
    • , Jakob Grove
    • , Eilis Hannon
    • , Annette M. Hartmann
    • , Barbara Heißerer
    • , Marinka Helthuis
    • , Henriette Thisted Horsdal
    • , Oddur Ingimarsson
    • , Karel Jollie
    • , James L. Kennedy
    • , Ole Köhler
    • , Bettina Konte
    • , Maren Lang
    • , Sophie E. Legge
    • , Cathryn Lewis
    • , James MacCabe
    • , Anil K. Malhotra
    • , Paul McCrone
    • , Sandra M. Meier
    • , Jonathan Mill
    • , Ole Mors
    • , Preben Bo Mortensen
    • , Markus M. Nöthen
    • , Michael C. O’Donovan
    • , Michael J. Owen
    • , Antonio F. Pardiñas
    • , Carsten B. Pedersen
    • , Marcella Rietschel
    • , Dan Rujescu
    • , Ameli Schwalber
    • , Engilbert Sigurdsson
    • , Holger J. Sørensen
    • , Benjamin Spencer
    • , Hreinn Stefansson
    • , Henrik Støvring
    • , Jana Strohmaier
    • , Patrick Sullivan
    • , Evangelos Vassos
    • , Moira Verbelen
    • , James T. R. Walters
    • , Thomas Werge
    • , David A. Collier
    • , Dan Rujescu
    • , George Kirov
    • , Michael J. Owen
    • , Michael C. O’Donovan
    •  & James T. R. Walters
  • Article | | Open Access

    A genome-wide association study (GWAS) of 58 traits using data from the Biobank Japan Project identifies 1,407 loci, 679 of which are novel. Comparison with disease GWASs and analysis of genetic correlations and cell-type enrichment show that these clinical measurements are relevant to human disease.

    • Masahiro Kanai
    • , Masato Akiyama
    • , Atsushi Takahashi
    • , Nana Matoba
    • , Yukihide Momozawa
    • , Masashi Ikeda
    • , Nakao Iwata
    • , Shiro Ikegawa
    • , Makoto Hirata
    • , Koichi Matsuda
    • , Michiaki Kubo
    • , Yukinori Okada
    •  & Yoichiro Kamatani
  • Article |

    Genome-wide association analysis using electronic health record data from >94,000 individuals identifies loci associated with plasma lipid concentrations. Longitudinal measurements allow for the calculation of genetic risk scores and increase the variance explained.

    • Thomas J. Hoffmann
    • , Elizabeth Theusch
    • , Tanushree Haldar
    • , Dilrini K. Ranatunga
    • , Eric Jorgenson
    • , Marisa W. Medina
    • , Mark N. Kvale
    • , Pui-Yan Kwok
    • , Catherine Schaefer
    • , Ronald M. Krauss
    • , Carlos Iribarren
    •  & Neil Risch
  • Article |

    The authors report a data-driven approach to phenotyping 3D facial shape. They apply their methodology to 2,329 individuals of European ancestry and identify 38 loci that associate with specific facial morphologies, some of which overlap with neural-crest-specific regulatory regions.

    • Peter Claes
    • , Jasmien Roosenboom
    • , Julie D. White
    • , Tomek Swigut
    • , Dzemila Sero
    • , Jiarui Li
    • , Myoung Keun Lee
    • , Arslan Zaidi
    • , Brooke C. Mattern
    • , Corey Liebowitz
    • , Laurel Pearson
    • , Tomás González
    • , Elizabeth J. Leslie
    • , Jenna C. Carlson
    • , Ekaterina Orlova
    • , Paul Suetens
    • , Dirk Vandermeulen
    • , Eleanor Feingold
    • , Mary L. Marazita
    • , John R. Shaffer
    • , Joanna Wysocka
    • , Mark D. Shriver
    •  & Seth M. Weinberg
  • Article |

    Analysis of chromatin accessibility and expression quantitative trait loci in stimulated or naïve macrophages identifies loci that constitutively alter chromatin but affect expression only after stimulation, thus indicating an effect on enhancer priming.

    • Kaur Alasoo
    • , Julia Rodrigues
    • , Subhankar Mukhopadhyay
    • , Andrew J. Knights
    • , Alice L. Mann
    • , Kousik Kundu
    • , Christine Hale
    • , Gordon Dougan
    •  & Daniel J. Gaffney
  • Article |

    The authors find that, in a high-fat diet (HFD) mouse model, levels of Stella protein are reduced in oocytes, leading to abnormal epigenetic patterning during development and to embryonic growth defects. Overexpression of Stella in oocytes from HFD-fed mice partially ameliorates developmental defects.

    • Longsen Han
    • , Chao Ren
    • , Ling Li
    • , Xiaoyan Li
    • , Juan Ge
    • , Haichao Wang
    • , Yi-Liang Miao
    • , Xuejiang Guo
    • , Kelle H. Moley
    • , Wenjie Shu
    •  & Qiang Wang
  • Article |

    The authors show that TET2 is recruited to chromatin by the RNA-binding protein PSPC1. PSPC1 and TET2 contribute to ERV and ERV-associated gene regulation by both transcriptional repression via histone deacetylases and post-transcriptional destabilization of ERV RNAs through 5hmC modification.

    • Diana Guallar
    • , Xianju Bi
    • , Jose Angel Pardavila
    • , Xin Huang
    • , Carmen Saenz
    • , Xianle Shi
    • , Hongwei Zhou
    • , Francesco Faiola
    • , Junjun Ding
    • , Phensinee Haruehanroengra
    • , Fan Yang
    • , Dan Li
    • , Carlos Sanchez-Priego
    • , Arven Saunders
    • , Feng Pan
    • , Victor Julian Valdes
    • , Kevin Kelley
    • , Miguel G. Blanco
    • , Lingyi Chen
    • , Huayan Wang
    • , Jia Sheng
    • , Mingjiang Xu
    • , Miguel Fidalgo
    • , Xiaohua Shen
    •  & Jianlong Wang
  • Article | | Open Access

    The authors report that DNA methylation coevolves with the DNA alkylation repair enzyme ALKB2 across eukaryotes. They also show that DNA methyltransferases cause alkylation damage in vitro and in vivo by introducing 3-methylcytosine into DNA.

    • Silvana Rošić
    • , Rachel Amouroux
    • , Cristina E. Requena
    • , Ana Gomes
    • , Max Emperle
    • , Toni Beltran
    • , Jayant K. Rane
    • , Sarah Linnett
    • , Murray E. Selkirk
    • , Philipp H. Schiffer
    • , Allison J. Bancroft
    • , Richard K. Grencis
    • , Albert Jeltsch
    • , Petra Hajkova
    •  & Peter Sarkies