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The Biology of Human Diseases, as Revealed Through Genomics

Guest Editors: Daniel MacArthur and Mark McCarthy

We are entering an era where the discovery of disease genes is conducted at the genome scale, and where integration of multiple types of ‘big data’ is used to elucidate variant-phenotype correlations. Additionally, a growing number of studies are identifying considerable overlap between common and rare human diseases, and further refining our understanding of their biology and the mechanisms by which they develop.

Genome Biology highlights important advances in human disease genomics with a special issue showcasing important work in this area.

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EDITORIAL
Human disease genomics: from variants to biology
We summarize the remarkable progress that has been made in the identification and functional characterization of DNA sequence variants associated with disease.
Mark I. McCarthy and Daniel G. MacArthur

Genome Biology 2017 18:20
Published on: 30 January 2017

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RESEARCH HIGHLIGHT
Human sex development: targeted technologies to improve diagnosis
A new study of disorders of sex development presents an improved targeted next-generation sequencing approach for their diagnosis.
Federica Buonocore and John C. Achermann

Genome Biology 2016 17:257
Published on: 15 December 2016

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MEETING REPORT
Ten years of the Genomics of Common Diseases: “The end of the beginning”
The 10th anniversary ‘Genomics of Common Diseases’ meeting was held in Baltimore, September 25-28, 2016. Professor Chris Haley reports from the meeting on progress and challenges in the field.
Chris S. Haley

Genome Biology 2016 17:254
Published on: 9 December 2016

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Review

REVIEW
Multi-omics approaches to disease
High-throughput technologies have revolutionized medical research. The advent of genotyping arrays enabled large-scale genome-wide association studies and methods for examining global transcript levels, which ...
Yehudit Hasin, Marcus Seldin and Aldons Lusis

Genome Biology 2017 18:83
Published on: 5 May 2017

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REVIEW
The impact of rare and low-frequency genetic variants in common disease
Despite thousands of genetic loci identified to date, a large proportion of genetic variation predisposing to complex disease and traits remains unaccounted for. Advances in sequencing technology enable focuse...
Lorenzo Bomba, Klaudia Walter and Nicole Soranzo

Genome Biology 2017 18:77
Published on: 27 April 2017

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REVIEW
The MHC locus and genetic susceptibility to autoimmune and infectious diseases
In the past 50 years, variants in the major histocompatibility complex (MHC) locus, also known as the human leukocyte antigen (HLA), have been reported as major risk factors for complex diseases. Recent advanc...
Vasiliki Matzaraki, Vinod Kumar, Cisca Wijmenga and Alexandra Zhernakova

Genome Biology 2017 18:76
Published on: 27 April 2017

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REVIEW
New insights into the generation and role of de novo mutations in health and disease
Aside from inheriting half of the genome of each of our parents, we are born with a small number of novel mutations that occurred during gametogenesis and postzygotically. Recent genome and exome sequencing st...
Rocio Acuna-Hidalgo, Joris A. Veltman and Alexander Hoischen

Genome Biology 2016 17:241
Published on: 28 November 2016

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REVIEW
Understanding rare and common diseases in the context of human evolution
The wealth of available genetic information is allowing the reconstruction of human demographic and adaptive history. Demography and purifying selection affect the purge of rare, deleterious mutations from the...
Lluis Quintana-Murci

Genome Biology 2016 17:225
Published on: 7 November 2016

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OPINION
The continuum of causality in human genetic disorders
Studies of human genetic disorders have traditionally followed a reductionist paradigm. Traits are defined as Mendelian or complex based on family pedigree and population data, whereas alleles are deemed rare,...
Nicholas Katsanis

Genome Biology 2016 17:233
Published on: 17 November 2016
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Research

RESEARCH
Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes
Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the dista...
Hongsheng Gui, Duco Schriemer, William W. Cheng, Rajendra K. Chauhan, Guillermo Antiňolo, Courtney Berrios, Marta Bleda, Alice S. Brooks, Rutger W. W. Brouwer, Alan J. Burns, Stacey S. Cherny, Joaquin Dopazo, Bart J. L. Eggen, Paola Griseri, Binta Jalloh, Thuy-Linh Le…

Genome Biology 2017 18:48
Published on: 8 March 2017

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RESEARCH
Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome
Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies.
Ryan L. Collins, Harrison Brand, Claire E. Redin, Carrie Hanscom, Caroline Antolik, Matthew R. Stone, Joseph T. Glessner, Tamara Mason, Giulia Pregno, Naghmeh Dorrani, Giorgia Mandrile, Daniela Giachino, Danielle Perrin, Cole Walsh, Michelle Cipicchio, Maura Costello…

Genome Biology 2017 18:36
Published on: 6 March 2017

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RESEARCH
Discovery and functional prioritization of Parkinson’s disease candidate genes from large-scale whole exome sequencing
Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson’s disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated pa...
Iris E. Jansen, Hui Ye, Sasja Heetveld, Marie C. Lechler, Helen Michels, Renée I. Seinstra, Steven J. Lubbe, Valérie Drouet, Suzanne Lesage, Elisa Majounie, J. Raphael Gibbs, Mike A. Nalls, Mina Ryten, Juan A. Botia, Jana Vandrovcova, Javier Simon-Sanchez…

Genome Biology 2017 18:22
Published on: 30 January 2017

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RESEARCH
Integrated genome-wide analysis of expression quantitative trait loci aids interpretation of genomic association studies
Identification of single nucleotide polymorphisms (SNPs) associated with gene expression levels, known as expression quantitative trait loci (eQTLs), may improve understanding of the functional role of phenoty...
Roby Joehanes, Xiaoling Zhang, Tianxiao Huan, Chen Yao, Sai-xia Ying, Quang Tri Nguyen, Cumhur Yusuf Demirkale, Michael L. Feolo, Nataliya R. Sharopova, Anne Sturcke, Alejandro A. Schäffer, Nancy Heard-Costa, Han Chen, Po-ching Liu, Richard Wang, Kimberly A. Woodhouse…

Genome Biology 2017 18:16
Published on: 25 January 2017

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RESEARCH
Transcriptomic signatures differentiate survival from fatal outcomes in humans infected with Ebola virus
In 2014, Western Africa experienced an unanticipated explosion of Ebola virus infections. What distinguishes fatal from non-fatal outcomes remains largely unknown, yet is key to optimising personalised treatme...
Xuan Liu, Emily Speranza, César Muñoz-Fontela, Sam Haldenby, Natasha Y. Rickett, Isabel Garcia-Dorival, Yongxiang Fang, Yper Hall, Elsa-Gayle Zekeng, Anja Lüdtke, Dong Xia, Romy Kerber, Ralf Krumkamp, Sophie Duraffour, Daouda Sissoko, John Kenny…

Genome Biology 2017 18:4
Published on: 19 January 2017

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RESEARCH
Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery
The relationship between monogenic and polygenic forms of epilepsy is poorly understood and the extent to which the genetic and acquired epilepsies share common pathways is unclear. Here, we use an integrated ...
Andree Delahaye-Duriez, Prashant Srivastava, Kirill Shkura, Sarah R. Langley, Liisi Laaniste, Aida Moreno-Moral, Bénédicte Danis, Manuela Mazzuferi, Patrik Foerch, Elena V. Gazina, Kay Richards, Steven Petrou, Rafal M. Kaminski, Enrico Petretto and Michael R. Johnson

Genome Biology 2016 17:245
Published on: 13 December 2016

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RESEARCH
Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease
Genome-wide association studies (GWAS) have revealed many susceptibility loci for complex genetic diseases. For most loci, the causal genes have not been identified. Currently, the identification of candidate ...
Claartje A. Meddens, Magdalena Harakalova, Noortje A. M. van den Dungen, Hassan Foroughi Asl, Hemme J. Hijma, Edwin P. J. G. Cuppen, Johan L. M. Björkegren, Folkert W. Asselbergs, Edward E. S. Nieuwenhuis and Michal Mokry

Genome Biology 2016 17:247
Published on: 30 November 2016

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RESEARCH
Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients recei...
Stefanie Eggers, Simon Sadedin, Jocelyn A. van den Bergen, Gorjana Robevska, Thomas Ohnesorg, Jacqueline Hewitt, Luke Lambeth, Aurore Bouty, Ingrid M. Knarston, Tiong Yang Tan, Fergus Cameron, George Werther, John Hutson, Michele O’Connell, Sonia R. Grover, Yves Heloury…

Genome Biology 2016 17:243
Published on: 29 November 2016

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RESEARCH
Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans
The 2’-5’ oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes (OAS1-3) involved in innate immune response. This region harbors high amounts of Neandertal ancestry in non-African populations; ye...
Aaron J. Sams, Anne Dumaine, Yohann Nédélec, Vania Yotova, Carolina Alfieri, Jerome E. Tanner, Philipp W. Messer and Luis B. Barreiro

Genome Biology 2016 17:246
Published on: 29 November 2016

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RESEARCH
Characterizing the morbid genome of ciliopathies
Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge...
Ranad Shaheen, Katarzyna Szymanska, Basudha Basu, Nisha Patel, Nour Ewida, Eissa Faqeih, Amal Al Hashem, Nada Derar, Hadeel Alsharif, Mohammed A. Aldahmesh, Anas M. Alazami, Mais Hashem, Niema Ibrahim, Firdous M. Abdulwahab, Rawda Sonbul, Hisham Alkuraya…

Genome Biology 2016 17:242
Published on: 28 November 2016

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RESEARCH
Whole genome sequence analysis of serum amino acid levels
Blood levels of amino acids are important biomarkers of disease and are influenced by synthesis, protein degradation, and gene–environment interactions. Whole genome sequence analysis of amino acid levels may ...
Bing Yu, Paul S. de Vries, Ginger A. Metcalf, Zhe Wang, Elena V. Feofanova, Xiaoming Liu, Donna Marie Muzny, Lynne E. Wagenknecht, Richard A. Gibbs, Alanna C. Morrison and Eric Boerwinkle

Genome Biology 2016 17:237
Published on: 24 November 2016

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RESEARCH
Revisiting the morbid genome of Mendelian disorders
The pathogenicity of many Mendelian variants has been challenged by large-scale sequencing efforts. However, many rare and benign “disease mutations” are difficult to analyze due to their rarity. The Saudi Ara...
Mohamed Abouelhoda, Tariq Faquih, Mohamed El-Kalioby and Fowzan S. Alkuraya

Genome Biology 2016 17:235
Published on: 24 November 2016

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RESEARCH
Integrative analysis of genetic data sets reveals a shared innate immune component in autism spectrum disorder and its co-morbidities
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder that tends to co-occur with other diseases, including asthma, inflammatory bowel disease, infections, cerebral palsy, dilated cardiomyopat...
Sumaiya Nazeen, Nathan P. Palmer, Bonnie Berger and Isaac S. Kohane

Genome Biology 2016 17:228
Published on: 14 November 2016

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RESEARCH
Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23
The identification of causal genes from genome-wide association studies (GWAS) is the next important step for the translation of genetic findings into biologically meaningful mechanisms of disease and potentia...
Amanda McGovern, Stefan Schoenfelder, Paul Martin, Jonathan Massey, Kate Duffus, Darren Plant, Annie Yarwood, Arthur G. Pratt, Amy E. Anderson, John D. Isaacs, Julie Diboll, Nishanthi Thalayasingam, Caroline Ospelt, Anne Barton, Jane Worthington, Peter Fraser…

Genome Biology 2016 17:212
Published on: 1 November 2016

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RESEARCH
GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition
Neuropsychiatric disorders are common forms of disability in humans. Despite recent progress in deciphering the genetics of these disorders, their phenotypic complexity continues to be a major challenge. Mende...
Hanan E. Shamseldin, Ikuo Masuho, Ahmed Alenizi, Suad Alyamani, Dipak N. Patil, Niema Ibrahim, Kirill A. Martemyanov and Fowzan S. Alkuraya

Genome Biology 2016 17:195
Published on: 27 September 2016

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RESEARCH
An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation
Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia,...
Eilis Hannon, Emma Dempster, Joana Viana, Joe Burrage, Adam R. Smith, Ruby Macdonald, David St Clair, Colette Mustard, Gerome Breen, Sebastian Therman, Jaakko Kaprio, Timothea Toulopoulou, Hilleke E. Hulshoff Pol, Marc M. Bohlken, Rene S. Kahn, Igor Nenadic…

Genome Biology 2016 17:176
Published on: 30 August 2016

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METHOD
cepip: context-dependent epigenomic weighting for prioritization of regulatory variants and disease-associated genes
It remains challenging to predict regulatory variants in particular tissues or cell types due to highly context-specific gene regulation. By connecting large-scale epigenomic profiles to expression quantitativ...
Mulin Jun Li, Miaoxin Li, Zipeng Liu, Bin Yan, Zhicheng Pan, Dandan Huang, Qian Liang, Dingge Ying, Feng Xu, Hongcheng Yao, Panwen Wang, Jean-Pierre A. Kocher, Zhengyuan Xia, Pak Chung Sham, Jun S. Liu and Junwen Wang

Genome Biology 2017 18:52
Published on: 16 March 2017

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METHOD
iRegNet3D: three-dimensional integrated regulatory network for the genomic analysis of coding and non-coding disease mutations
The mechanistic details of most disease-causing mutations remain poorly explored within the context of regulatory networks. We present a high-resolution three-dimensional integrated regulatory network (iRegNet...
Siqi Liang, Nathaniel D. Tippens, Yaoda Zhou, Matthew Mort, Peter D. Stenson, David N. Cooper and Haiyuan Yu

Genome Biology 2017 18:10
Published on: 18 January 2017

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METHOD
GAVIN: Gene-Aware Variant INterpretation for medical sequencing
We present Gene-Aware Variant INterpretation (GAVIN), a new method that accurately classifies variants for clinical diagnostic purposes. Classifications are based on gene-specific calibrations of allele freque...
K. Joeri van der Velde, Eddy N. de Boer, Cleo C. van Diemen, Birgit Sikkema-Raddatz, Kristin M. Abbott, Alain Knopperts, Lude Franke, Rolf H. Sijmons, Tom J. de Koning, Cisca Wijmenga, Richard J. Sinke and Morris A. Swertz

Genome Biology 2017 18:6
Published on: 16 January 2017

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METHOD
DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases
Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inf...
Symen Ligthart, Carola Marzi, Stella Aslibekyan, Michael M. Mendelson, Karen N. Conneely, Toshiko Tanaka, Elena Colicino, Lindsay L. Waite, Roby Joehanes, Weihua Guan, Jennifer A. Brody, Cathy Elks, Riccardo Marioni, Min A. Jhun, Golareh Agha, Jan Bressler…

Genome Biology 2016 17:255
Published on: 12 December 2016

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METHOD
DIVAN: accurate identification of non-coding disease-specific risk variants using multi-omics profiles
Understanding the link between non-coding sequence variants, identified in genome-wide association studies, and the pathophysiology of complex diseases remains challenging due to a lack of annotations in non-c...
Li Chen, Peng Jin and Zhaohui S. Qin

Genome Biology 2016 17:252
Published on: 6 December 2016

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