Search Our Scientific Publications & Authors

Nat Genet 2019 Apr 16. Epub 2019 Apr 16.

Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.

In the version of this article initially published, grant PF-17-201-01-TBG from the American Cancer Society to author Erica C. Pehrsson was not included in the Acknowledgements. The error has been corrected in the HTML and PDF versions of the article. Read More

Nat Genet 2019 Apr 15. Epub 2019 Apr 15.

Department of Human Genetics, McGill University, Montréal, Québec, Canada.

In the version of this article initially published, in Fig. 5a, the data in the right column of 'DAAM2 gRNA1' were incorrectly plotted as circles indicating 'untreated' rather than as squares indicating 'treated'. The error has been corrected in the HTML and PDF versions of the article. Read More

Nat Genet 2019 Apr 15. Epub 2019 Apr 15.

deCODE Genetics, Reykjavik, Iceland.

Nat Genet 2019 Apr 15. Epub 2019 Apr 15.

Department of Biomedical Informatics and Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.

Mutations in BRCA1 and/or BRCA2 (BRCA1/2) are the most common indication of deficiency in the homologous recombination (HR) DNA repair pathway. However, recent genome-wide analyses have shown that the same pattern of mutations found in BRCA1/2-mutant tumors is also present in several other tumors. Here, we present a new computational tool called Signature Multivariate Analysis (SigMA), which can be used to accurately detect the mutational signature associated with HR deficiency from targeted gene panels. Read More

Nat Genet 2019 Apr 15. Epub 2019 Apr 15.

Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA.

BMP/SMAD signaling is a crucial regulator of intestinal differentiation. However, the molecular underpinnings of the BMP pathway in this context are unknown. Here, we characterize the mechanism by which BMP/SMAD signaling drives enterocyte differentiation. Read More

Nat Genet 2019 Apr 15. Epub 2019 Apr 15.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.

Precise control of plant stem cell proliferation is necessary for the continuous and reproducible development of plant organs. The peptide ligand CLAVATA3 (CLV3) and its receptor protein kinase CLAVATA1 (CLV1) maintain stem cell homeostasis within a deeply conserved negative feedback circuit. In Arabidopsis, CLV1 paralogs also contribute to homeostasis, by compensating for the loss of CLV1 through transcriptional upregulation. Read More

Nat Genet 2019 Apr 8. Epub 2019 Apr 8.

CREA-Research Centre for Genomics and Bioinformatics, Fiorenzuola d'Arda, Italy.

The domestication of wild emmer wheat led to the selection of modern durum wheat, grown mainly for pasta production. We describe the 10.45 gigabase (Gb) assembly of the genome of durum wheat cultivar Svevo. Read More

Nat Genet 2019 Apr 8. Epub 2019 Apr 8.

Department of Biological Sciences, Columbia University, New York, NY, USA.

In numerous applications, from working with animal models to mapping the genetic basis of human disease susceptibility, knowing whether a single disrupting mutation in a gene is likely to be deleterious is useful. With this goal in mind, a number of measures have been developed to identify genes in which protein-truncating variants (PTVs), or other types of mutations, are absent or kept at very low frequency in large population samples-genes that appear 'intolerant' to mutation. One measure in particular, the probability of being loss-of-function intolerant (pLI), has been widely adopted. Read More

Nat Genet 2019 Apr 4. Epub 2019 Apr 4.

Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan.

In the version of the paper initially published, Fig. 5a was inadvertently duplicated and presented as both Fig. 5a and 5f, and the correct image for Fig. Read More

Nat Genet 2019 04 29;51(4):636-648. Epub 2019 Mar 29.

Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Read More

Nat Genet 2019 04 29;51(4):649-658. Epub 2019 Mar 29.

Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG) allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. Read More

Nat Genet 2019 04 29;51(4):694-704. Epub 2019 Mar 29.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Read More

Nat Genet 2019 04 29;51(4):675-682. Epub 2019 Mar 29.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Transcriptome-wide association studies using predicted expression have identified thousands of genes whose locally regulated expression is associated with complex traits and diseases. In this work, we show that linkage disequilibrium induces significant gene-trait associations at non-causal genes as a function of the expression quantitative trait loci weights used in expression prediction. We introduce a probabilistic framework that models correlation among transcriptome-wide association study signals to assign a probability for every gene in the risk region to explain the observed association signal. Read More

Nat Genet 2019 04 29;51(4):611-617. Epub 2019 Mar 29.

Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.

Transposable elements (TEs) are an abundant and rich genetic resource of regulatory sequences. Cryptic regulatory elements within TEs can be epigenetically reactivated in cancer to influence oncogenesis in a process termed onco-exaptation. However, the prevalence and impact of TE onco-exaptation events across cancer types are poorly characterized. Read More

Nat Genet 2019 04 29;51(4):592-599. Epub 2019 Mar 29.

Department of Computer Science, Stanford University, Stanford, CA, USA.

Transcriptome-wide association studies (TWAS) integrate genome-wide association studies (GWAS) and gene expression datasets to identify gene-trait associations. In this Perspective, we explore properties of TWAS as a potential approach to prioritize causal genes at GWAS loci, by using simulations and case studies of literature-curated candidate causal genes for schizophrenia, low-density-lipoprotein cholesterol and Crohn's disease. We explore risk loci where TWAS accurately prioritizes the likely causal gene as well as loci where TWAS prioritizes multiple genes, some likely to be non-causal, owing to sharing of expression quantitative trait loci (eQTL). Read More

Nat Genet 2019 04;51(4):579

Nat Genet 2019 04 29;51(4):584-591. Epub 2019 Mar 29.

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Polygenic risk scores (PRS) are poised to improve biomedical outcomes via precision medicine. However, the major ethical and scientific challenge surrounding clinical implementation of PRS is that those available today are several times more accurate in individuals of European ancestry than other ancestries. This disparity is an inescapable consequence of Eurocentric biases in genome-wide association studies, thus highlighting that-unlike clinical biomarkers and prescription drugs, which may individually work better in some populations but do not ubiquitously perform far better in European populations-clinical uses of PRS today would systematically afford greater improvement for European-descent populations. Read More

Nat Genet 2019 04;51(4):580-581

Department of Neurology, University of Michigan, Ann Arbor, MI, USA.

Nat Genet 2019 04;51(4):581-583

Human Genetics, Wellcome Sanger Institute, Hinxton, UK.

Nat Genet 2019 04;51(4):766

Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.

In the version of this article initially published, in the graph keys in Fig. 1i, the colors indicating 'Ob' and 'Ad' were red and blue, respectively, but should have been blue and red, respectively; the shapes indicating 'MUS' and 'BM' were a triangle and a square, respectively, but should have been a square and a triangle, respectively. The errors have been corrected in the HTML and PDF versions of the article. Read More

Nat Genet 2019 04 25;51(4):659-674. Epub 2019 Mar 25.

Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. Read More

Nat Genet 2019 04 18;51(4):627-635. Epub 2019 Mar 18.

Department of Molecular Biology, Princeton University, Princeton, NJ, USA.

Photosynthetic organisms provide food and energy for nearly all life on Earth, yet half of their protein-coding genes remain uncharacterized. Characterization of these genes could be greatly accelerated by new genetic resources for unicellular organisms. Here we generated a genome-wide, indexed library of mapped insertion mutants for the unicellular alga Chlamydomonas reinhardtii. Read More

Nat Genet 2019 04 18;51(4):739-748. Epub 2019 Mar 18.

Institute of Crop Science, Plant Precision Breeding Academy, Zhejiang Provincial Key Laboratory of Crop Genetic Resources, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China.

Allotetraploid cotton is an economically important natural-fiber-producing crop worldwide. After polyploidization, Gossypium hirsutum L. evolved to produce a higher fiber yield and to better survive harsh environments than Gossypium barbadense, which produces superior-quality fibers. Read More

Nat Genet 2019 04 18;51(4):749-754. Epub 2019 Mar 18.

Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.

Whole-genome sequencing of DNA from single cells has the potential to reshape our understanding of mutational heterogeneity in normal and diseased tissues. However, a major difficulty is distinguishing amplification artifacts from biologically derived somatic mutations. Here, we describe linked-read analysis (LiRA), a method that accurately identifies somatic single-nucleotide variants (sSNVs) by using read-level phasing with nearby germline heterozygous polymorphisms, thereby enabling the characterization of mutational signatures and estimation of somatic mutation rates in single cells. Read More

Nat Genet 2019 04 11;51(4):618-626. Epub 2019 Mar 11.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Perturbations to mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complexes have been widely implicated as driving events in cancer. One such perturbation is the dual loss of the SMARCA4 and SMARCA2 ATPase subunits in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), SMARCA4-deficient thoracic sarcomas and dedifferentiated endometrial carcinomas. However, the consequences of dual ATPase subunit loss on mSWI/SNF complex subunit composition, chromatin targeting, DNA accessibility and gene expression remain unknown. Read More

Nat Genet 2019 04 11;51(4):683-693. Epub 2019 Mar 11.

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Widespread linkage disequilibrium and incomplete annotation of cell-to-cell state variation represent substantial challenges to elucidating mechanisms of trait-associated genetic variation. Here we perform genetic fine-mapping for blood cell traits in the UK Biobank to identify putative causal variants. These variants are enriched in genes encoding proteins in trait-relevant biological pathways and in accessible chromatin of hematopoietic progenitors. Read More

Nat Genet 2019 04;51(4):766

The State Key Laboratory of Cell Biology, CAS Center for Excellence on Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

In the version of this article initially published, the following grant numbers and recipients were missing from the Acknowledgements: XDB19000000 to H.J. and B. Read More

Nat Genet 2019 04;51(4):765

Department of Plant Sciences, University of California-Davis, Davis, CA, USA.

In the version of this article originally published, author Joshua R. Puzey was incorrectly listed as having affiliation 7 (School of Plant Sciences, University of Arizona, Tucson, AZ, USA); affiliation 6 (Department of Biology, College of William and Mary, Williamsburg, VA, USA) is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article. Read More

Nat Genet 2019 04 4;51(4):716-727. Epub 2019 Mar 4.

Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.

Mesenchymal (stromal) stem cells (MSCs) constitute populations of mesodermal multipotent cells involved in tissue regeneration and homeostasis in many different organs. Here we performed comprehensive characterization of the transcriptional and epigenomic changes associated with osteoblast and adipocyte differentiation of human MSCs. We demonstrate that adipogenesis is driven by considerable remodeling of the chromatin landscape and de novo activation of enhancers, whereas osteogenesis involves activation of preestablished enhancers. Read More

Nat Genet 2019 04 4;51(4):705-715. Epub 2019 Mar 4.

Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA.

Cancer genomes are frequently characterized by numerical and structural chromosomal abnormalities. Here we integrated a centromere-specific inactivation approach with selection for a conditionally essential gene, a strategy termed CEN-SELECT, to systematically interrogate the structural landscape of mis-segregated chromosomes. We show that single-chromosome mis-segregation into a micronucleus can directly trigger a broad spectrum of genomic rearrangement types. Read More

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Read More

Nat Genet 2019 03;51(3):365

Nat Genet 2019 03;51(3):372-373

Center for Applied Genetic Technologies, University of Georgia, Athens, GA, USA.

Nat Genet 2019 04;51(4):764

Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA.

In the version of this article initially published, affiliation 38 incorrectly read "ICNU-Nephrology and Urology Department, Barcelona, Spain"; "Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain" is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article. Read More

Nat Genet 2019 04;51(4):764-765

Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.

In the version of this article initially published, in Fig. 4b, the shared environmental variance (c) values for all MaTCH functional domains except 'all traits' were erroneously estimated because of a coding error. Figure 4 has been revised to include corrected c estimates in the data in panel b as well as the number of phenotypes in CaTCH and MaTCH functional domains in the y axes of panels a and b; the Fig. Read More

Nat Genet 2019 03 25;51(3):387-393. Epub 2019 Feb 25.

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identified 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmed their effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923 cases and 47,610 controls), physician-diagnosed insomnia in the Partners Biobank (n = 2,217 cases and 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Read More

Nat Genet 2019 03 25;51(3):394-403. Epub 2019 Feb 25.

Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, the Netherlands.

Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains limited. Here, we use a large genetic association sample (n = 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints. Read More

Nat Genet 2019 Feb 25. Epub 2019 Feb 25.

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Nat Genet 2019 03 25;51(3):568-576. Epub 2019 Feb 25.

Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Read More

Nat Genet 2019 04 25;51(4):755-763. Epub 2019 Feb 25.

Department of Computer Science, Stanford University, Stanford, CA, USA.

Exome analysis of patients with a likely monogenic disease does not identify a causal variant in over half of cases. Splice-disrupting mutations make up the second largest class of known disease-causing mutations. Each individual (singleton) exome harbors over 500 rare variants of unknown significance (VUS) in the splicing region. Read More

Nat Genet 2019 03 25;51(3):494-505. Epub 2019 Feb 25.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. Read More

Nat Genet 2019 03 25;51(3):481-493. Epub 2019 Feb 25.

Department of Health Sciences, University of Leicester, Leicester, UK.

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Read More

Nat Genet 2019 03 25;51(3):529-540. Epub 2019 Feb 25.

Laboratory for Developmental Epigenetics, RIKEN Center for Biosystems Dynamics Research (BDR), Kobe, Japan.

Here, we report a single-cell DNA replication sequencing method, scRepli-seq, a genome-wide methodology that measures copy number differences between replicated and unreplicated DNA. Using scRepli-seq, we demonstrate that replication-domain organization is conserved among individual mouse embryonic stem cells (mESCs). Differentiated mESCs exhibited distinct profiles, which were also conserved among cells. Read More

Nat Genet 2019 03 25;51(3):431-444. Epub 2019 Feb 25.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Read More

Nat Genet 2019 03 25;51(3):541-547. Epub 2019 Feb 25.

Department of Plant Sciences, University of California-Davis, Davis, California, USA.

Cultivated strawberry emerged from the hybridization of two wild octoploid species, both descendants from the merger of four diploid progenitor species into a single nucleus more than 1 million years ago. Here we report a near-complete chromosome-scale assembly for cultivated octoploid strawberry (Fragaria × ananassa) and uncovered the origin and evolutionary processes that shaped this complex allopolyploid. We identified the extant relatives of each diploid progenitor species and provide support for the North American origin of octoploid strawberry. Read More

Nat Genet 2019 03;51(3):369-371

Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Nat Genet 2019 03;51(3):366

Department of Neurology, Oslo University Hospital, Oslo, Norway.

Nat Genet 2019 03;51(3):367-368

Centre for Applied Neurogenetics, University of British Columbia, Vancouver, British Columbia, Canada.

Nat Genet 2019 03;51(3):577

Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.

In the version of this article initially published, in the Methods section 'Statistics and data analysis', subsection 'Measuring entropy with INSIGHT', the equation for the maximized log likelihood incorrectly duplicated the equation for entropy; the equation read but should have read. The error has been corrected in the HTML and PDF versions of the article. Read More

Nat Genet 2019 03 18;51(3):452-469. Epub 2019 Feb 18.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Read More