Analyses

  • Analysis |

    Mendelian randomization (MR) and colocalization analyses are used to estimate causal effects of 1,002 plasma proteins on 225 phenotypes. Evidence from drug developmental programs shows that target-indication pairs with MR and colocalization support were more likely to be approved, highlighting the value of this approach for prioritizing therapeutic targets.

    • Jie Zheng
    • , Valeriia Haberland
    • , Denis Baird
    • , Venexia Walker
    • , Philip C. Haycock
    • , Mark R. Hurle
    • , Alex Gutteridge
    • , Pau Erola
    • , Yi Liu
    • , Shan Luo
    • , Jamie Robinson
    • , Tom G. Richardson
    • , James R. Staley
    • , Benjamin Elsworth
    • , Stephen Burgess
    • , Benjamin B. Sun
    • , John Danesh
    • , Heiko Runz
    • , Joseph C. Maranville
    • , Hannah M. Martin
    • , James Yarmolinsky
    • , Charles Laurin
    • , Michael V. Holmes
    • , Jimmy Z. Liu
    • , Karol Estrada
    • , Rita Santos
    • , Linda McCarthy
    • , Dawn Waterworth
    • , Matthew R. Nelson
    • , George Davey Smith
    • , Adam S. Butterworth
    • , Gibran Hemani
    • , Robert A. Scott
    •  & Tom R. Gaunt
  • Analysis
    | Open Access

    This analysis presents a harmonized meta-knowledgebase to facilitate clinical interpretation of somatic genomic variants in cancer. This community-based project highlights the need for cooperative efforts to curate clinical interpretations of somatic variants for robust practice of precision oncology.

    • Alex H. Wagner
    • , Brian Walsh
    • , Georgia Mayfield
    • , David Tamborero
    • , Dmitriy Sonkin
    • , Kilannin Krysiak
    • , Jordi Deu-Pons
    • , Ryan P. Duren
    • , Jianjiong Gao
    • , Julie McMurry
    • , Sara Patterson
    • , Catherine del Vecchio Fitz
    • , Beth A. Pitel
    • , Ozman U. Sezerman
    • , Kyle Ellrott
    • , Jeremy L. Warner
    • , Damian T. Rieke
    • , Tero Aittokallio
    • , Ethan Cerami
    • , Deborah I. Ritter
    • , Lynn M. Schriml
    • , Robert R. Freimuth
    • , Melissa Haendel
    • , Gordana Raca
    • , Subha Madhavan
    • , Michael Baudis
    • , Jacques S. Beckmann
    • , Rodrigo Dienstmann
    • , Debyani Chakravarty
    • , Xuan Shirley Li
    • , Susan Mockus
    • , Olivier Elemento
    • , Nikolaus Schultz
    • , Nuria Lopez-Bigas
    • , Mark Lawler
    • , Jeremy Goecks
    • , Malachi Griffith
    • , Obi L. Griffith
    •  & Adam A. Margolin
  • Analysis |

    Genetic analyses of depression based on minimal phenotyping identify nonspecific genetic risk factors shared between major depressive disorder (MDD) and other psychiatric conditions, suggesting that this approach may have limited ability to identify pathways specific to MDD.

    • Na Cai
    • , Joana A. Revez
    • , Mark J. Adams
    • , Till F. M. Andlauer
    • , Gerome Breen
    • , Enda M. Byrne
    • , Toni-Kim Clarke
    • , Andreas J. Forstner
    • , Hans J. Grabe
    • , Steven P. Hamilton
    • , Douglas F. Levinson
    • , Cathryn M. Lewis
    • , Glyn Lewis
    • , Nicholas G. Martin
    • , Yuri Milaneschi
    • , Ole Mors
    • , Bertram Müller-Myhsok
    • , Brenda W. J. H. Penninx
    • , Roy H. Perlis
    • , Giorgio Pistis
    • , James B. Potash
    • , Martin Preisig
    • , Jianxin Shi
    • , Jordan W. Smoller
    • , Fabien Streit
    • , Henning Tiemeier
    • , Rudolf Uher
    • , Sandra Van der Auwera
    • , Alexander Viktorin
    • , Myrna M. Weissman
    • , Kenneth S. Kendler
    •  & Jonathan Flint
  • Analysis |

    Assessing heritability models using summary statistics from genome-wide association studies of 31 human traits shows that the Baseline LD model is realistic and can be improved by incorporating features from the LDAK model.

    • Doug Speed
    • , John Holmes
    •  & David J. Balding
  • Analysis
    | Open Access

    Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

    • Isidro Cortés-Ciriano
    • , Jake June-Koo Lee
    • , Ruibin Xi
    • , Dhawal Jain
    • , Youngsook L. Jung
    • , Lixing Yang
    • , Dmitry Gordenin
    • , Leszek J. Klimczak
    • , Cheng-Zhong Zhang
    • , David S. Pellman
    • , Kadir C. Akdemir
    • , Eva G. Alvarez
    • , Adrian Baez-Ortega
    • , Rameen Beroukhim
    • , Paul C. Boutros
    • , David D. L. Bowtell
    • , Benedikt Brors
    • , Kathleen H. Burns
    • , Peter J. Campbell
    • , Kin Chan
    • , Ken Chen
    • , Isidro Cortés-Ciriano
    • , Ana Dueso-Barroso
    • , Andrew J. Dunford
    • , Paul A. Edwards
    • , Xavier Estivill
    • , Dariush Etemadmoghadam
    • , Lars Feuerbach
    • , J. Lynn Fink
    • , Milana Frenkel-Morgenstern
    • , Dale W. Garsed
    • , Mark Gerstein
    • , Dmitry A. Gordenin
    • , David Haan
    • , James E. Haber
    • , Julian M. Hess
    • , Barbara Hutter
    • , Marcin Imielinski
    • , David T. W. Jones
    • , Young Seok Ju
    • , Marat D. Kazanov
    • , Leszek J. Klimczak
    • , Youngil Koh
    • , Jan O. Korbel
    • , Kiran Kumar
    • , Eunjung Alice Lee
    • , Jake June-Koo Lee
    • , Yilong Li
    • , Andy G. Lynch
    • , Geoff Macintyre
    • , Florian Markowetz
    • , Iñigo Martincorena
    • , Alexander Martinez-Fundichely
    • , Satoru Miyano
    • , Hidewaki Nakagawa
    • , Fabio C. P. Navarro
    • , Stephan Ossowski
    • , Peter J. Park
    • , John V. Pearson
    • , Montserrat Puiggròs
    • , Karsten Rippe
    • , Nicola D. Roberts
    • , Steven A. Roberts
    • , Bernardo Rodriguez-Martin
    • , Steven E. Schumacher
    • , Ralph Scully
    • , Mark Shackleton
    • , Nikos Sidiropoulos
    • , Lina Sieverling
    • , Chip Stewart
    • , David Torrents
    • , Jose M. C. Tubio
    • , Izar Villasante
    • , Nicola Waddell
    • , Jeremiah A. Wala
    • , Joachim Weischenfeldt
    • , Lixing Yang
    • , Xiaotong Yao
    • , Sung-Soo Yoon
    • , Jorge Zamora
    • , Cheng-Zhong Zhang
    •  & Peter J. Park
  • Analysis
    | Open Access

    Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

    • Yuan Yuan
    • , Young Seok Ju
    • , Youngwook Kim
    • , Jun Li
    • , Yumeng Wang
    • , Christopher J. Yoon
    • , Yang Yang
    • , Inigo Martincorena
    • , Chad J. Creighton
    • , John N. Weinstein
    • , Yanxun Xu
    • , Leng Han
    • , Hyung-Lae Kim
    • , Hidewaki Nakagawa
    • , Keunchil Park
    • , Peter J. Campbell
    •  & Han Liang
  • Analysis |

    Pan-cancer genomic analyses based on HLA affinity predictions show that apparent neoantigen depletion signals in untreated tumors become negligible after correction for trinucleotide-based mutational signatures.

    • Jimmy Van den Eynden
    • , Alejandro Jiménez-Sánchez
    • , Martin L. Miller
    •  & Erik Larsson
  • Analysis |

    Genome-wide analyses in 19,629 individuals identify 365 independent variants associated with brain volumetric phenotypes. The study provides insight into the overlapping genetic architecture of brain volume measures and cognitive and mental health traits.

    • Bingxin Zhao
    • , Tianyou Luo
    • , Tengfei Li
    • , Yun Li
    • , Jingwen Zhang
    • , Yue Shan
    • , Xifeng Wang
    • , Liuqing Yang
    • , Fan Zhou
    • , Ziliang Zhu
    •  & Hongtu Zhu
  • Analysis |

    Analysis of whole-genome sequencing and expression data for 17 tissues identifies short tandem repeats whose repeat number is associated with gene expression (eSTRs). Specific eSTRs are implicated in different complex traits through colocalization analysis with known genome-wide association study signals.

    • Stephanie Feupe Fotsing
    • , Jonathan Margoliash
    • , Catherine Wang
    • , Shubham Saini
    • , Richard Yanicky
    • , Sharona Shleizer-Burko
    • , Alon Goren
    •  & Melissa Gymrek
  • Analysis |

    Exome sequencing of a worldwide panel of 487 wheat genotypes, including landraces, cultivars and modern varieties, sheds light on wheat genomic diversity and the evolution of modern bread wheat.

    • Caroline Pont
    • , Thibault Leroy
    • , Michael Seidel
    • , Alessandro Tondelli
    • , Wandrille Duchemin
    • , David Armisen
    • , Daniel Lang
    • , Daniela Bustos-Korts
    • , Nadia Goué
    • , François Balfourier
    • , Márta Molnár-Láng
    • , Jacob Lage
    • , Benjamin Kilian
    • , Hakan Özkan
    • , Darren Waite
    • , Sarah Dyer
    • , Thomas Letellier
    • , Michael Alaux
    • , Joanne Russell
    • , Beat Keller
    • , Fred van Eeuwijk
    • , Manuel Spannagl
    • , Klaus F. X. Mayer
    • , Robbie Waugh
    • , Nils Stein
    • , Luigi Cattivelli
    • , Georg Haberer
    • , Gilles Charmet
    •  & Jérôme Salse
  • Analysis |

    This comprehensive pancancer analysis of RNA-sequencing data from bulk tumors defines the landscape of tumor-infiltrating B cell–receptor repertoires and highlights new mechanisms of tumor immune evasion through genetic alterations.

    • Xihao Hu
    • , Jian Zhang
    • , Jin Wang
    • , Jingxin Fu
    • , Taiwen Li
    • , Xiaoqi Zheng
    • , Binbin Wang
    • , Shengqing Gu
    • , Peng Jiang
    • , Jingyu Fan
    • , Xiaomin Ying
    • , Jing Zhang
    • , Michael C. Carroll
    • , Kai W. Wucherpfennig
    • , Nir Hacohen
    • , Fan Zhang
    • , Peng Zhang
    • , Jun S. Liu
    • , Bo Li
    •  & X. Shirley Liu
  • Analysis |

    Including patient-specific information about nearby somatic and germline alterations improves the accuracy of neoantigen prediction, potentially impacting cancer vaccine design.

    • Jasreet Hundal
    • , Susanna Kiwala
    • , Yang-Yang Feng
    • , Connor J. Liu
    • , Ramaswamy Govindan
    • , William C. Chapman
    • , Ravindra Uppaluri
    • , S. Joshua Swamidass
    • , Obi L. Griffith
    • , Elaine R. Mardis
    •  & Malachi Griffith
  • Analysis |

    GeneATLAS is a web resource that presents genetic association results for 118 non-binary and 660 binary traits using UK Biobank data. This atlas allows researchers to query these results without incurring high computational costs.

    • Oriol Canela-Xandri
    • , Konrad Rawlik
    •  & Albert Tenesa
  • Analysis |

    The authors extend stratified linkage disequilibrium score regression to partition the heritability of both low-frequency and common variants in 40 heritable traits from the UK Biobank, providing insights into low-frequency and rare variant functional architectures.

    • Steven Gazal
    • , Po-Ru Loh
    • , Hilary K. Finucane
    • , Andrea Ganna
    • , Armin Schoech
    • , Shamil Sunyaev
    •  & Alkes L. Price
  • Analysis |

    Analysis of mRNA splicing in the dorsolateral prefrontal cortex from two cohorts established to study aging identifies variations in pre-mRNA splicing events that are associated with Alzheimer’s disease.

    • Towfique Raj
    • , Yang I. Li
    • , Garrett Wong
    • , Jack Humphrey
    • , Minghui Wang
    • , Satesh Ramdhani
    • , Ying-Chih Wang
    • , Bernard Ng
    • , Ishaan Gupta
    • , Vahram Haroutunian
    • , Eric E. Schadt
    • , Tracy Young-Pearse
    • , Sara Mostafavi
    • , Bin Zhang
    • , Pamela Sklar
    • , David A. Bennett
    •  & Philip L. De Jager
  • Analysis |

    Signed linkage disequilibrium profile regression is a new method for detecting directional effects of genomic annotations on disease risk. The results implicate new causal disease genes and can suggest mechanisms underlying the effects of causal genes on disease.

    • Yakir A. Reshef
    • , Hilary K. Finucane
    • , David R. Kelley
    • , Alexander Gusev
    • , Dylan Kotliar
    • , Jacob C. Ulirsch
    • , Farhad Hormozdiari
    • , Joseph Nasser
    • , Luke O’Connor
    • , Bryce van de Geijn
    • , Po-Ru Loh
    • , Sharon R. Grossman
    • , Gaurav Bhatia
    • , Steven Gazal
    • , Pier Francesco Palamara
    • , Luca Pinello
    • , Nick Patterson
    • , Ryan P. Adams
    •  & Alkes L Price
  • Analysis |

    Analysis of GTEx, cancer and autism data sets shows that cis-regulatory variation can modify the penetrance of coding variants. Deleterious coding variants on regulatory haplotypes resulting in high expression are enriched in disease cohorts and selected against in general populations.

    • Stephane E. Castel
    • , Alejandra Cervera
    • , Pejman Mohammadi
    • , François Aguet
    • , Ferran Reverter
    • , Aaron Wolman
    • , Roderic Guigo
    • , Ivan Iossifov
    • , Ana Vasileva
    •  & Tuuli Lappalainen
  • Analysis |

    SAIGE (Scalable and Accurate Implementation of GEneralized mixed model) is a generalized mixed model association test that can efficiently analyze large data sets while controlling for unbalanced case-control ratios and sample relatedness, as shown by applying SAIGE to the UK Biobank data for > 1,400 binary phenotypes.

    • Wei Zhou
    • , Jonas B. Nielsen
    • , Lars G. Fritsche
    • , Rounak Dey
    • , Maiken E. Gabrielsen
    • , Brooke N. Wolford
    • , Jonathon LeFaive
    • , Peter VandeHaar
    • , Sarah A. Gagliano
    • , Aliya Gifford
    • , Lisa A. Bastarache
    • , Wei-Qi Wei
    • , Joshua C. Denny
    • , Maoxuan Lin
    • , Kristian Hveem
    • , Hyun Min Kang
    • , Goncalo R. Abecasis
    • , Cristen J. Willer
    •  & Seunggeun Lee
  • Analysis |

    The authors identify whole-genome doubling (WGD) in 30% of ~10,000 sequenced tumors from patients with advanced cancer. WGD correlates with increased risk of death across cancer types.

    • Craig M. Bielski
    • , Ahmet Zehir
    • , Alexander V. Penson
    • , Mark T. A. Donoghue
    • , Walid Chatila
    • , Joshua Armenia
    • , Matthew T. Chang
    • , Alison M. Schram
    • , Philip Jonsson
    • , Chaitanya Bandlamudi
    • , Pedram Razavi
    • , Gopa Iyer
    • , Mark E. Robson
    • , Zsofia K. Stadler
    • , Nikolaus Schultz
    • , Jose Baselga
    • , David B. Solit
    • , David M. Hyman
    • , Michael F. Berger
    •  & Barry S. Taylor
  • Analysis |

    A new set of functional annotations based on fine-mapped molecular quantitative trait loci from GTEx and BLUEPRINT consortium data are enriched for disease heritability across 41 diseases and complex traits.

    • Farhad Hormozdiari
    • , Steven Gazal
    • , Bryce van de Geijn
    • , Hilary K. Finucane
    • , Chelsea J.-T. Ju
    • , Po-Ru Loh
    • , Armin Schoech
    • , Yakir Reshef
    • , Xuanyao Liu
    • , Luke O’Connor
    • , Alexander Gusev
    • , Eleazar Eskin
    •  & Alkes L. Price
  • Analysis |

    Analysis of individuals with neurodevelopmental disorders (NDDs) with epilepsy identifies 33 genes with a significant excess of de novo variants. Comparison of rates of de novo variants between NDDs with or without epilepsy highlights differences between these phenotypic groups.

    • Henrike O. Heyne
    • , Tarjinder Singh
    • , Hannah Stamberger
    • , Rami Abou Jamra
    • , Hande Caglayan
    • , Dana Craiu
    • , Peter De Jonghe
    • , Renzo Guerrini
    • , Katherine L. Helbig
    • , Bobby P. C. Koeleman
    • , Jack A. Kosmicki
    • , Tarja Linnankivi
    • , Patrick May
    • , Hiltrud Muhle
    • , Rikke S. Møller
    • , Bernd A. Neubauer
    • , Aarno Palotie
    • , Manuela Pendziwiat
    • , Pasquale Striano
    • , Sha Tang
    • , Sitao Wu
    • , Zaid Afawi
    • , Carolien de Kovel
    • , Petia Dimova
    • , Tania Djémié
    • , Milda Endziniene
    • , Dorota Hoffman-Zacharska
    • , Johanna Jähn
    • , Christian Korff
    • , Anna-Elina Lehesjoki
    • , Carla Marini
    • , Stefanie H. Müller
    • , Deb Pal
    • , Niklas Schwarz
    • , Kaja Selmer
    • , Jose Serratosa
    • , Ulrich Stephani
    • , Katalin Štěrbová
    • , Arvid Suls
    • , Steffen Syrbe
    • , Inga Talvik
    • , Shan Tang
    • , Sarah von Spiczak
    • , Federico Zara
    • , Annapurna Poduri
    • , Yvonne G. Weber
    • , Sarah Weckhuysen
    • , Sanjay M. Sisodiya
    • , Mark J. Daly
    • , Ingo Helbig
    • , Dennis Lal
    •  & Johannes R. Lemke
  • Analysis |

    This analysis compares methods for estimating the heritability and genetic architecture of complex traits using whole-genome data. The results provide guidance for best practices and proper interpretation of published heritability estimates.

    • Luke M. Evans
    • , Rasool Tahmasbi
    • , Scott I. Vrieze
    • , Gonçalo R. Abecasis
    • , Sayantan Das
    • , Steven Gazal
    • , Douglas W. Bjelland
    • , Teresa R. de Candia
    • , Michael E. Goddard
    • , Benjamin M. Neale
    • , Jian Yang
    • , Peter M. Visscher
    •  & Matthew C. Keller
  • Analysis |

    MACHINA is an algorithm that analyzes metastatic cancer sequence data to simultaneously infer clone trees and migration histories. Analysis of different metastatic cancer datasets provides more evidence for simple, rather than complex, migration patterns.

    • Mohammed El-Kebir
    • , Gryte Satas
    •  & Benjamin J. Raphael
  • Analysis |

    This study presents a framework to evaluate rare and de novo variation from whole-genome sequencing (WGS). The work suggests that robust results from WGS studies will require large cohorts and strategies that consider the substantial multiple-testing burden.

    • Donna M. Werling
    • , Harrison Brand
    • , Joon-Yong An
    • , Matthew R. Stone
    • , Lingxue Zhu
    • , Joseph T. Glessner
    • , Ryan L. Collins
    • , Shan Dong
    • , Ryan M. Layer
    • , Eirene Markenscoff-Papadimitriou
    • , Andrew Farrell
    • , Grace B. Schwartz
    • , Harold Z. Wang
    • , Benjamin B. Currall
    • , Xuefang Zhao
    • , Jeanselle Dea
    • , Clif Duhn
    • , Carolyn A. Erdman
    • , Michael C. Gilson
    • , Rachita Yadav
    • , Robert E. Handsaker
    • , Seva Kashin
    • , Lambertus Klei
    • , Jeffrey D. Mandell
    • , Tomasz J. Nowakowski
    • , Yuwen Liu
    • , Sirisha Pochareddy
    • , Louw Smith
    • , Michael F. Walker
    • , Matthew J. Waterman
    • , Xin He
    • , Arnold R. Kriegstein
    • , John L. Rubenstein
    • , Nenad Sestan
    • , Steven A. McCarroll
    • , Benjamin M. Neale
    • , Hilary Coon
    • , A. Jeremy Willsey
    • , Joseph D. Buxbaum
    • , Mark J. Daly
    • , Matthew W. State
    • , Aaron R. Quinlan
    • , Gabor T. Marth
    • , Kathryn Roeder
    • , Bernie Devlin
    • , Michael E. Talkowski
    •  & Stephan J. Sanders
  • Analysis |

    BayesS estimates SNP-based heritability, polygenicity, and the relationship between effect size and minor allele frequency using genome-wide SNP data. Applying BayesS to UK Biobank data identifies signatures of natural selection for 23 complex traits.

    • Jian Zeng
    • , Ronald de Vlaming
    • , Yang Wu
    • , Matthew R. Robinson
    • , Luke R. Lloyd-Jones
    • , Loic Yengo
    • , Chloe X. Yap
    • , Angli Xue
    • , Julia Sidorenko
    • , Allan F. McRae
    • , Joseph E. Powell
    • , Grant W. Montgomery
    • , Andres Metspalu
    • , Tonu Esko
    • , Greg Gibson
    • , Naomi R. Wray
    • , Peter M. Visscher
    •  & Jian Yang
  • Analysis |

    A new method tests whether disease heritability is enriched near genes with high tissue-specific expression. The authors use gene expression data together with GWAS summary statistics for 48 diseases and traits to identify disease-relevant tissues.

    • Hilary K. Finucane
    • , Yakir A. Reshef
    • , Verneri Anttila
    • , Kamil Slowikowski
    • , Alexander Gusev
    • , Andrea Byrnes
    • , Steven Gazal
    • , Po-Ru Loh
    • , Caleb Lareau
    • , Noam Shoresh
    • , Giulio Genovese
    • , Arpiar Saunders
    • , Evan Macosko
    • , Samuela Pollack
    • , John R. B. Perry
    • , Jason D. Buenrostro
    • , Bradley E. Bernstein
    • , Soumya Raychaudhuri
    • , Steven McCarroll
    • , Benjamin M. Neale
    •  & Alkes L. Price
  • Analysis |

    This analysis of cancer sequencing data identifies a reduced somatic mutation rate in exons and shows that this phenomenon is due to higher mismatch-repair activity in exons as compared to introns. These findings have implications for the understanding of mutational and DNA repair processes and for studying the evolution of both tumors and species.

    • Joan Frigola
    • , Radhakrishnan Sabarinathan
    • , Loris Mularoni
    • , Ferran Muiños
    • , Abel Gonzalez-Perez
    •  & Núria López-Bigas
  • Analysis |

    This study presents a new approach to estimate the tissues contributing to the genetic causality for complex traits and diseases. The method assesses tissue sharing of eQTLs among 44 tissues and then uses these tissue-sharing estimates to infer the tissues where trait-associated variants likely exert their function.

    • Halit Ongen
    • , Andrew A Brown
    • , Olivier Delaneau
    • , Nikolaos I Panousis
    • , Alexandra C Nica
    •  & Emmanouil T Dermitzakis
  • Analysis |

    This large-scale analysis of copy number alterations (CNAs) in patient-derived xenografts (PDXs) across 24 cancer types shows that new CNAs accumulate quickly and that the specific CNAs acquired during passaging differ from those acquired during tumor evolution in patients, suggesting that PDX tumors are under distinct selection pressures from tumors in human hosts.

    • Uri Ben-David
    • , Gavin Ha
    • , Yuen-Yi Tseng
    • , Noah F Greenwald
    • , Coyin Oh
    • , Juliann Shih
    • , James M McFarland
    • , Bang Wong
    • , Jesse S Boehm
    • , Rameen Beroukhim
    •  & Todd R Golub
  • Analysis |

    Steven Gazal, Alkes Price and colleagues extend stratified LD score regression to continuous annotations. They analyze summary statistics from 56 complex diseases and traits and find that SNPs with low levels of linkage disequilibrium have larger per-SNP heritability, consistent with the action of negative selection on deleterious variants that affect complex traits.

    • Steven Gazal
    • , Hilary K Finucane
    • , Nicholas A Furlotte
    • , Po-Ru Loh
    • , Pier Francesco Palamara
    • , Xuanyao Liu
    • , Armin Schoech
    • , Brendan Bulik-Sullivan
    • , Benjamin M Neale
    • , Alexander Gusev
    •  & Alkes L Price
  • Analysis |

    Kevin Yip and colleagues report a method for determining the target genes of enhancers in specific cells and tissues by combining global trends across many samples with sample-specific information, and considering the joint effect of multiple enhancers. They apply their method to reconstruct enhancer–target networks in 935 samples of human primary cells, tissues and cell lines.

    • Qin Cao
    • , Christine Anyansi
    • , Xihao Hu
    • , Liangliang Xu
    • , Lei Xiong
    • , Wenshu Tang
    • , Myth T S Mok
    • , Chao Cheng
    • , Xiaodan Fan
    • , Mark Gerstein
    • , Alfred S L Cheng
    •  & Kevin Y Yip
  • Analysis |

    Andrey Rzhetsky and colleagues analyze electronic medical records from over one-third of the US population to estimate disease heritability and to determine the genetic and environmental contributions to disease variance. They obtain 84 new heritability estimates and find that the genetic correlation values for disease pairs differ from their environmental correlation values.

    • Kanix Wang
    • , Hallie Gaitsch
    • , Hoifung Poon
    • , Nancy J Cox
    •  & Andrey Rzhetsky
  • Analysis |

    Gil McVean and colleagues present a new Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to analyze genetic variants against UK Biobank disease phenotypes derived from self-reporting and hospital episode statistics. Their method displays increased power to detect genetic effects over other approaches and identifies novel associations between classical HLA alleles and common immune-mediated diseases.

    • Adrian Cortes
    • , Calliope A Dendrou
    • , Allan Motyer
    • , Luke Jostins
    • , Damjan Vukcevic
    • , Alexander Dilthey
    • , Peter Donnelly
    • , Stephen Leslie
    • , Lars Fugger
    •  & Gil McVean
  • Analysis |

    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.

    • 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
    • , 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
  • Analysis |

    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.

    • 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
    • , Aarno Palotie
    • , Patrick F Sullivan
    • , Michael C O'Donovan
    • , Michael J Owen
    •  & Jeffrey C Barrett
  • Analysis |

    Elise Robinson and colleagues present the polygenic transmission disequilibrium test (pTDT) for evaluating transmission of polygenic risk in family-based study designs. The authors apply pTDT to a cohort of autism spectrum disorder (ASD) families and find that common polygenic variation acts additively with de novo variants to contribute to ASD risk.

    • Daniel J Weiner
    • , Emilie M Wigdor
    • , Stephan Ripke
    • , Raymond K Walters
    • , Jack A Kosmicki
    • , Jakob Grove
    • , Kaitlin E Samocha
    • , Jacqueline I Goldstein
    • , Aysu Okbay
    • , Jonas Bybjerg-Grauholm
    • , Thomas Werge
    • , David M Hougaard
    • , Jacob Taylor
    • , Marie Bækvad-Hansen
    • , Ashley Dumont
    • , Christine Hansen
    • , Thomas F Hansen
    • , Daniel Howrigan
    • , Manuel Mattheisen
    • , Jennifer Moran
    • , Ole Mors
    • , Merete Nordentoft
    • , Bent Nørgaard-Pedersen
    • , Timothy Poterba
    • , Jesper Poulsen
    • , Christine Stevens
    • , Verneri Anttila
    • , Peter Holmans
    • , Hailiang Huang
    • , Lambertus Klei
    • , Phil H Lee
    • , Sarah E Medland
    • , Benjamin Neale
    • , Lauren A Weiss
    • , Lonnie Zwaigenbaum
    • , Timothy W Yu
    • , Kerstin Wittemeyer
    • , A Jeremy Willsey
    • , Ellen M Wijsman
    • , Thomas H Wassink
    • , Regina Waltes
    • , Christopher A Walsh
    • , Simon Wallace
    • , Jacob A S Vorstman
    • , Veronica J Vieland
    • , Astrid M Vicente
    • , Herman van Engeland
    • , Kathryn Tsang
    • , Ann P Thompson
    • , Peter Szatmari
    • , Oscar Svantesson
    • , Stacy Steinberg
    • , Kari Stefansson
    • , Hreinn Stefansson
    • , Matthew W State
    • , Latha Soorya
    • , Teimuraz Silagadze
    • , Stephen W Scherer
    • , Gerard D Schellenberg
    • , Sven Sandin
    • , Evald Saemundsen
    • , Guy A Rouleau
    • , Bernadette Rogé
    • , Kathryn Roeder
    • , Wendy Roberts
    • , Jennifer Reichert
    • , Abraham Reichenberg
    • , Karola Rehnström
    • , Regina Regan
    • , Fritz Poustka
    • , Christopher S Poultney
    • , Joseph Piven
    • , Dalila Pinto
    • , Margaret A Pericak-Vance
    • , Milica Pejovic-Milovancevic
    • , Marianne G Pedersen
    • , Carsten B Pedersen
    • , Andrew D Paterson
    • , Jeremy R Parr
    • , Alistair T Pagnamenta
    • , Guiomar Oliveira
    • , John I Nurnberger
    • , Merete Nordentoft
    • , Michael T Murtha
    • , Susana Mouga
    • , Ole Mors
    • , Eric M Morrow
    • , Daniel Moreno De Luca
    • , Anthony P Monaco
    • , Nancy Minshew
    • , Alison Merikangas
    • , William M McMahon
    • , Susan G McGrew
    • , Manuel Mattheisen
    • , Igor Martsenkovsky
    • , Donna M Martin
    • , Shrikant M Mane
    • , Pall Magnusson
    • , Tiago Magalhaes
    • , Elena Maestrini
    • , Jennifer K Lowe
    • , Catherine Lord
    • , Pat Levitt
    • , Christa Lese Martin
    • , David H Ledbetter
    • , Marion Leboyer
    • , Ann S Le Couteur
    • , Christine Ladd-Acosta
    • , Alexander Kolevzon
    • , Sabine M Klauck
    • , Suma Jacob
    • , Bozenna Iliadou
    • , Christina M Hultman
    • , Irva Hertz-Picciotto
    • , Robert Hendren
    • , Christine S Hansen
    • , Jonathan L Haines
    • , Stephen J Guter
    • , Dorothy E Grice
    • , Jonathan M Green
    • , Andrew Green
    • , Arthur P Goldberg
    • , Christopher Gillberg
    • , John Gilbert
    • , Louise Gallagher
    • , Christine M Freitag
    • , Eric Fombonne
    • , Susan E Folstein
    • , Bridget Fernandez
    • , M Daniele Fallin
    • , A Gulhan Ercan-Sencicek
    • , Sean Ennis
    • , Frederico Duque
    • , Eftichia Duketis
    • , Richard Delorme
    • , Silvia De Rubeis
    • , Maretha V De Jonge
    • , Geraldine Dawson
    • , Michael L Cuccaro
    • , Catarina T Correia
    • , Judith Conroy
    • , Inês C Conceição
    • , Andreas G Chiocchetti
    • , Patrícia B S Celestino-Soper
    • , Jillian Casey
    • , Rita M Cantor
    • , Cátia Café
    • , Sean Brennan
    • , Thomas Bourgeron
    • , Patrick F Bolton
    • , Sven Bölte
    • , Nadia Bolshakova
    • , Catalina Betancur
    • , Raphael Bernier
    • , Arthur L Beaudet
    • , Agatino Battaglia
    • , Vanessa H Bal
    • , Gillian Baird
    • , Anthony J Bailey
    • , Marie Bækvad-Hansen
    • , Joel S Bader
    • , Elena Bacchelli
    • , Evdokia Anagnostou
    • , David Amaral
    • , Joana Almeida
    • , Joseph D Buxbaum
    • , Aravinda Chakravarti
    • , Edwin H Cook
    • , Hilary Coon
    • , Daniel H Geschwind
    • , Michael Gill
    • , Hakon Hakonarson
    • , Joachim Hallmayer
    • , Aarno Palotie
    • , Susan Santangelo
    • , James S Sutcliffe
    • , Dan E Arking
    • , David Skuse
    • , Bernie Devlin
    • , Richard Anney
    • , Stephan J Sanders
    • , Somer Bishop
    • , Preben Bo Mortensen
    • , Anders D Børglum
    • , George Davey Smith
    • , Mark J Daly
    •  & Elise B Robinson
  • Analysis |

    Michael Schatz, David Tuveson and colleagues analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas. They find recurrent noncoding regulatory mutations that correlate with differential expression of proximal genes and find that the strongest regulatory elements are more frequently mutated, suggesting a selective advantage for mutations in these regions.

    • Michael E Feigin
    • , Tyler Garvin
    • , Peter Bailey
    • , Nicola Waddell
    • , David K Chang
    • , David R Kelley
    • , Shimin Shuai
    • , Steven Gallinger
    • , John D McPherson
    • , Sean M Grimmond
    • , Ekta Khurana
    • , Lincoln D Stein
    • , Andrew V Biankin
    • , Michael C Schatz
    •  & David A Tuveson
  • Analysis |

    Jérôme Salse and colleagues report a reconstruction of the most recent common ancestor of modern monocots and eudicots, which dates to the late Triassic era. Their results represent a resource for plant geneticists to extend findings from model species to crops.

    • Florent Murat
    • , Alix Armero
    • , Caroline Pont
    • , Christophe Klopp
    •  & Jérôme Salse
  • Analysis |

    Örjan Carlborg and colleagues analyze genotype and phenotype data from 4,390 yeast segregants from a cross between laboratory and vineyard strains to estimate how higher-order genetic interactions contribute to complex trait variation. They find networks of epistatic loci and show that accounting for these interactions leads to more accurate phenotypic predictions.

    • Simon K G Forsberg
    • , Joshua S Bloom
    • , Meru J Sadhu
    • , Leonid Kruglyak
    •  & Örjan Carlborg
  • Analysis |

    Mark Daly and colleagues use population reference samples to refine the role of de novo protein-truncating variants in neurodevelopmental disorders. They show that variants independently observed in population reference samples do not contribute substantively to neurodevelopmental risk, and they use a loss-of-function intolerance metric to identify a small subset of genes that contain the entire observed signal of associated de novo protein-truncating variants in these disorders.

    • Jack A Kosmicki
    • , Kaitlin E Samocha
    • , Daniel P Howrigan
    • , Stephan J Sanders
    • , Kamil Slowikowski
    • , Monkol Lek
    • , Konrad J Karczewski
    • , David J Cutler
    • , Bernie Devlin
    • , Kathryn Roeder
    • , Joseph D Buxbaum
    • , Benjamin M Neale
    • , Daniel G MacArthur
    • , Dennis P Wall
    • , Elise B Robinson
    •  & Mark J Daly
  • Analysis |

    Siyuan Zheng, Roel Verhaak and colleagues report an analysis of telomere lengths and somatic alterations in telomere-related pathways across 31 cancer types. Their study provides an overview of the molecular mechanisms driving TERT expression and activation of the ALT pathway, and identifies a subset of tumors with neither detectable TERT expression nor somatic alterations in ATRX or DAXX.

    • Floris P Barthel
    • , Wei Wei
    • , Ming Tang
    • , Emmanuel Martinez-Ledesma
    • , Xin Hu
    • , Samirkumar B Amin
    • , Kadir C Akdemir
    • , Sahil Seth
    • , Xingzhi Song
    • , Qianghu Wang
    • , Tara Lichtenberg
    • , Jian Hu
    • , Jianhua Zhang
    • , Siyuan Zheng
    •  & Roel G W Verhaak
  • Analysis |

    Serena Nik-Zainal and colleagues present a detailed analysis of somatic rearrangements in 560 breast cancers. They highlight 33 rearrangement hotspots characterized mainly by large tandem duplications and show that these hotspots are enriched in breast cancer germline susceptibility loci and breast-specific super-enhancer elements.

    • Dominik Glodzik
    • , Sandro Morganella
    • , Helen Davies
    • , Peter T Simpson
    • , Yilong Li
    • , Xueqing Zou
    • , Javier Diez-Perez
    • , Johan Staaf
    • , Ludmil B Alexandrov
    • , Marcel Smid
    • , Arie B Brinkman
    • , Inga Hansine Rye
    • , Hege Russnes
    • , Keiran Raine
    • , Colin A Purdie
    • , Sunil R Lakhani
    • , Alastair M Thompson
    • , Ewan Birney
    • , Hendrik G Stunnenberg
    • , Marc J van de Vijver
    • , John W M Martens
    • , Anne-Lise Børresen-Dale
    • , Andrea L Richardson
    • , Gu Kong
    • , Alain Viari
    • , Douglas Easton
    • , Gerard Evan
    • , Peter J Campbell
    • , Michael R Stratton
    •  & Serena Nik-Zainal
  • Analysis |

    Peter Campbell, Hartmut Döhner and colleagues present an analysis of genetic mutations and clinical information from 1,540 patients with acute myeloid leukemia, demonstrating the utility of clinical knowledge banks for personalized medicine. They show that use of their approach could reduce the number of hematopoietic cell transplants in patients with AML by up to 25% while maintaining survival rates.

    • Moritz Gerstung
    • , Elli Papaemmanuil
    • , Inigo Martincorena
    • , Lars Bullinger
    • , Verena I Gaidzik
    • , Peter Paschka
    • , Michael Heuser
    • , Felicitas Thol
    • , Niccolo Bolli
    • , Peter Ganly
    • , Arnold Ganser
    • , Ultan McDermott
    • , Konstanze Döhner
    • , Richard F Schlenk
    • , Hartmut Döhner
    •  & Peter J Campbell
  • Analysis |

    Jimmy Liu and colleagues perform genome-wide association by proxy (GWAX) in a large population cohort by replacing cases with their first-degree relatives. They apply GWAX to 12 common diseases and show its utility by identifying new risk loci for Alzheimer's disease, coronary artery disease and type 2 diabetes.

    • Jimmy Z Liu
    • , Yaniv Erlich
    •  & Joseph K Pickrell
  • Analysis |

    Nada Jabado, Jacek Majewski and colleagues identify mutations in multiple histone H3 genes causing recurrent p.Lys36Met alterations in head and neck squamous cell carcinomas. They show that tumors with these p.Lys36Met alterations correspond to a specific DNA methylation cluster along with tumors harboring previously described mutations in NSD1.

    • Simon Papillon-Cavanagh
    • , Chao Lu
    • , Tenzin Gayden
    • , Leonie G Mikael
    • , Denise Bechet
    • , Christina Karamboulas
    • , Laurie Ailles
    • , Jason Karamchandani
    • , Dylan M Marchione
    • , Benjamin A Garcia
    • , Ilan Weinreb
    • , David Goldstein
    • , Peter W Lewis
    • , Octavia Maria Dancu
    • , Sandeep Dhaliwal
    • , William Stecho
    • , Christopher J Howlett
    • , Joe S Mymryk
    • , John W Barrett
    • , Anthony C Nichols
    • , C David Allis
    • , Jacek Majewski
    •  & Nada Jabado