Search Our Scientific Publications & Authors

Nat Genet 2019 Feb 18. 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

Nat Genet 2019 Feb 18. Epub 2019 Feb 18.

Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, TX, USA.

Streptococcus pyogenes causes 700 million human infections annually worldwide, yet, despite a century of intensive effort, there is no licensed vaccine against this bacterium. Although a number of large-scale genomic studies of bacterial pathogens have been published, the relationships among the genome, transcriptome, and virulence in large bacterial populations remain poorly understood. We sequenced the genomes of 2,101 emm28 S. Read More

Nat Genet 2019 Feb 18. Epub 2019 Feb 18.

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

Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity. However, the causal relationships remain largely unresolved. We leveraged information from 952 normoglycemic individuals for whom genome-wide genotyping, gut metagenomic sequence and fecal short-chain fatty acid (SCFA) levels were available, then combined this information with genome-wide-association summary statistics for 17 metabolic and anthropometric traits. Read More

Nat Genet 2019 Feb 18. Epub 2019 Feb 18.

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.

Characterizing the stem cells responsible for lung repair and regeneration is important for the treatment of pulmonary diseases. Recently, a unique cell population located at the bronchioalveolar-duct junctions has been proposed to comprise endogenous stem cells for lung regeneration. However, the role of bronchioalveolar stem cells (BASCs) in vivo remains debated, and the contribution of such cells to lung regeneration is not known. Read More

Nat Genet 2019 Feb 11. Epub 2019 Feb 11.

Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Tumor-infiltrating B cells are an important component in the microenvironment but have unclear anti-tumor effects. We enhanced our previous computational algorithm TRUST to extract the B cell immunoglobulin hypervariable regions from bulk tumor RNA-sequencing data. TRUST assembled more than 30 million complementarity-determining region 3 sequences of the B cell heavy chain (IgH) from The Cancer Genome Atlas. Read More

Nat Genet 2019 Feb 11. Epub 2019 Feb 11.

Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

Genome-wide association studies (GWAS) have identified genetic variants at 34 loci contributing to age-related macular degeneration (AMD). We generated transcriptional profiles of postmortem retinas from 453 controls and cases at distinct stages of AMD and integrated retinal transcriptomes, covering 13,662 protein-coding and 1,462 noncoding genes, with genotypes at more than 9 million common SNPs for expression quantitative trait loci (eQTL) analysis of a tissue not included in Genotype-Tissue Expression (GTEx) and other large datasets. Cis-eQTL analysis identified 10,474 genes under genetic regulation, including 4,541 eQTLs detected only in the retina. Read More

Nat Genet 2019 Feb 4. Epub 2019 Feb 4.

MRC cancer unit, Hutchison/MRC research Centre, University of Cambridge, Cambridge, UK.

Esophageal adenocarcinoma (EAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving EAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. Using a cohort of 551 genomically characterized EACs with matched RNA sequencing data, we discovered 77 EAC driver genes and 21 noncoding driver elements. Read More

Nat Genet 2019 Feb 4. Epub 2019 Feb 4.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

To understand the genetics of type 2 diabetes in people of Japanese ancestry, we conducted A meta-analysis of four genome-wide association studies (GWAS; 36,614 cases and 155,150 controls of Japanese ancestry). We identified 88 type 2 diabetes-associated loci (P < 5.0 × 10) with 115 independent signals (P < 5. Read More

Nat Genet 2019 Feb;51(2):197

Nat Genet 2019 Jan 29. Epub 2019 Jan 29.

Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, School of Philosophy, Psychology and Language Sciences, University of Edinburgh, Edinburgh, UK.

In the version of this article initially published, in Table 2, the descriptions of pathways and definitions in the first and last columns did not correctly correspond to the values in the other columns. The error has been corrected in the HTML and PDF versions of the article. Read More

Nat Genet 2019 Jan 28. Epub 2019 Jan 28.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.

To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype-phenotype associations across 52 phenotypes. Read More

Nat Genet 2019 Jan 28. Epub 2019 Jan 28.

Swiss Institute for Experimental Cancer Research (ISREC), School of Life Science, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

Chromatin is organized into topologically associating domains (TADs) enriched in distinct histone marks. In cancer, gain-of-function mutations in the gene encoding the enhancer of zeste homolog 2 protein (EZH2) lead to a genome-wide increase in histone-3 Lys27 trimethylation (H3K27me3) associated with transcriptional repression. However, the effects of these epigenetic changes on the structure and function of chromatin domains have not been explored. Read More

Nat Genet 2019 Feb 28;51(2):343-353. Epub 2019 Jan 28.

Human Genetics, Wellcome Sanger Institute, Hinxton, UK.

Loci discovered by genome-wide association studies predominantly map outside protein-coding genes. The interpretation of the functional consequences of non-coding variants can be greatly enhanced by catalogs of regulatory genomic regions in cell lines and primary tissues. However, robust and readily applicable methods are still lacking by which to systematically evaluate the contribution of these regions to genetic variation implicated in diseases or quantitative traits. Read More

Nat Genet 2019 Feb;51(2):200-201

School of Agriculture, Food and Wine, University of Adelaide, Adelaide, South Australia, Australia.

Nat Genet 2019 Feb 21;51(2):230-236. Epub 2019 Jan 21.

Human Genetics, Wellcome Genome Campus, Wellcome Sanger Institute, Cambridge, UK.

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Read More

Nat Genet 2019 Feb;51(2):364

Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.

In the version of this article initially published, the statement "there are no pan-genomes for any other animal or plant species" was incorrect. The statement has been corrected to "there are no reported pan-genomes for any other animal species, to our knowledge." We thank David Edwards for bringing this error to our attention. Read More

Nat Genet 2019 Feb;51(2):364

Gene Expression and Biophysics Group, Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

In the version of this article initially published, '+' and '-' labels were missing from the graph keys at the bottom of Fig. 8d. The error has been corrected in the HTML and PDF versions of the article. Read More

Nat Genet 2019 Feb 14;51(2):245-257. Epub 2019 Jan 14.

Department of Economics, University of Toronto, Toronto, Ontario, Canada.

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. Read More

Nat Genet 2019 Feb 14;51(2):354-362. Epub 2019 Jan 14.

Seven Bridges Genomics, Inc, Cambridge, MA, USA.

The human reference genome serves as the foundation for genomics by providing a scaffold for alignment of sequencing reads, but currently only reflects a single consensus haplotype, thus impairing analysis accuracy. Here we present a graph reference genome implementation that enables read alignment across 2,800 diploid genomes encompassing 12.6 million SNPs and 4. Read More

Nat Genet 2019 Jan 14. Epub 2019 Jan 14.

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (N = 2,370,390), and found 304 significant independent signals. Read More

Nat Genet 2019 Feb 14;51(2):267-276. Epub 2019 Jan 14.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. Read More

Nat Genet 2019 Feb 14;51(2):202-206. Epub 2019 Jan 14.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Read More

Nat Genet 2019 Feb 14;51(2):327-334. Epub 2019 Jan 14.

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

We analysed a large health insurance dataset to assess the genetic and environmental contributions of 560 disease-related phenotypes in 56,396 twin pairs and 724,513 sibling pairs out of 44,859,462 individuals that live in the United States. We estimated the contribution of environmental risk factors (socioeconomic status (SES), air pollution and climate) in each phenotype. Mean heritability (h = 0. Read More

Nat Genet 2019 Feb 14;51(2):285-295. Epub 2019 Jan 14.

Mammalian Developmental Epigenetics Group, Genetics and Developmental Biology Unit, Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, Paris, France.

During X-chromosome inactivation (XCI), one of the two X-inactivation centers (Xics) upregulates the noncoding RNA Xist to initiate chromosomal silencing in cis. How one Xic is chosen to upregulate Xist remains unclear. Models proposed include localization of one Xic at the nuclear envelope or transient homologous Xic pairing followed by asymmetric transcription factor distribution at Xist's antisense Xite/Tsix locus. Read More

Nat Genet 2019 Feb 14;51(2):237-244. Epub 2019 Jan 14.

Department of Psychology, University of Minnesota Twin Cities, Minneapolis, MN, USA.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders. They are heritable and etiologically related behaviors that have been resistant to gene discovery efforts. In sample sizes up to 1. Read More

Nat Genet 2019 Feb 14;51(2):308-318. Epub 2019 Jan 14.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. Read More

Nat Genet 2019 Feb 14;51(2):296-307. Epub 2019 Jan 14.

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

Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5. Read More

Nat Genet 2019 Jan 14. Epub 2019 Jan 14.

Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.

Inbreeding depression confers reduced fitness among the offspring of genetic relatives. As a clonally propagated crop, potato (Solanum tuberosum L.) suffers from severe inbreeding depression; however, the genetic basis of inbreeding depression in potato is largely unknown. Read More

Nat Genet 2019 Feb;51(2):363

Institute of Cancer Research, London, UK.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article. Read More

Nat Genet 2019 Jan 7. Epub 2019 Jan 7.

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

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). Read More

Nat Genet 2019 Feb 7;51(2):217-223. Epub 2019 Jan 7.

Institute of Molecular Biology (IMB), Mainz, Germany.

R-loops are DNA-RNA hybrids enriched at CpG islands (CGIs) that can regulate chromatin states. How R-loops are recognized and interpreted by specific epigenetic readers is unknown. Here we show that GADD45A (growth arrest and DNA damage protein 45A) binds directly to R-loops and mediates local DNA demethylation by recruiting TET1 (ten-eleven translocation 1). Read More

Nat Genet 2019 Feb;51(2):198

Cardiovascular Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Nat Genet 2019 Feb;51(2):198-199

Pediatric Cardiology, Medical College of Wisconsin, Milwaukee, WI, USA.

Nat Genet 2019 Feb 31;51(2):258-266. Epub 2018 Dec 31.

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

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1. Read More

Nat Genet 2019 Jan 21;51(1):51-62. Epub 2018 Dec 21.

Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells. Read More

Nat Genet 2019 Jan 21;51(1):117-127. Epub 2018 Dec 21.

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

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Read More

Nat Genet 2019 Jan;51(1)

Application of deep learning to genomic datasets is an exciting area that is rapidly developing and is primed to revolutionize genome analysis. We embrace the potential that deep learning holds for understanding genome biology, and we encourage further advances in this area, extending to all aspects of genomics research. Read More

Nat Genet 2019 Feb;51(2):364

Illumina Artificial Intelligence Laboratory, Illumina Inc, San Diego, CA, USA.

In the version of this article originally published, the name of author Serafim Batzoglou was misspelled. The error has been corrected in the HTML and PDF versions of the article. Read More

Nat Genet 2019 Feb 17;51(2):335-342. Epub 2018 Dec 17.

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

Here we ask the question "How much information do epigenomic datasets provide about human genomic function?" We consider nine epigenomic features across 115 cell types and measure information about function as a reduction in entropy under a probabilistic evolutionary model fitted to human and nonhuman primate genomes. Several epigenomic features yield more information in combination than they do individually. We find that the entropy in human genetic variation predominantly reflects a balance between mutation and neutral drift. Read More

Nat Genet 2019 Jan 17;51(1):19-25. Epub 2018 Dec 17.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Recent advances in single-cell and single-molecule epigenomic technologies now enable the study of genome regulation and dynamics at unprecedented resolution. In this Perspective, we highlight some of these transformative technologies and discuss how they have been used to identify new modes of gene regulation. We also contrast these assays with recent advances in single-cell transcriptomics and argue for the essential role of epigenomic technologies in both understanding cellular diversity and discovering gene regulatory mechanisms. Read More

Nat Genet 2019 Jan 17;51(1):106-116. Epub 2018 Dec 17.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.

We combined de novo mutation (DNM) data from 10,927 individuals with developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive (LGD) mutations. Of these genes, 124 reach exome-wide significance (P < 5 × 10) for DNM. Intersecting these results with copy number variation (CNV) morbidity data shows an enrichment for genomic disorder regions (30/253, likelihood ratio (LR) +1. Read More

Nat Genet 2019 Jan;51(1):196

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

In the version of this article originally published, there was an error in the second-to-last sentence of the abstract. In this sentence, the final phrase "to identify carriers of first-wave gene mutation carriers" should have instead read "to identify carriers of first-wave gene mutation." The error has been corrected in the HTML and PDF versions of the paper. Read More

Nat Genet 2019 Jan;51(1):196

Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

In the version of this article initially published, reference 10 incorrectly cited Seplyarskiy, V. B. et al. Read More

Nat Genet 2019 Jan 10;51(1):138-150. Epub 2018 Dec 10.

Gene Expression and Biophysics Group, Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Accumulation of trimethylation of histone H3 at lysine 4 (H3K4me3) on immune-related gene promoters underlies robust transcription during trained immunity. However, the molecular basis for this remains unknown. Here we show three-dimensional chromatin topology enables immune genes to engage in chromosomal contacts with a subset of long noncoding RNAs (lncRNAs) we have defined as immune gene-priming lncRNAs (IPLs). Read More

Nat Genet 2019 Feb 10;51(2):207-216. Epub 2018 Dec 10.

Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA, USA.

Seventy percent of breast cancers express the estrogen receptor (ER), and agents that target the ER are the mainstay of treatment. However, virtually all people with ER breast cancer develop resistance to ER-directed agents in the metastatic setting. Beyond mutations in the ER itself, which occur in 25-30% of people treated with aromatase inhibitors, knowledge about clinical resistance mechanisms remains incomplete. Read More

Nat Genet 2019 Jan 10;51(1):88-95. Epub 2018 Dec 10.

Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.

Deep catalogs of genetic variation from thousands of humans enable the detection of intraspecies constraint by identifying coding regions with a scarcity of variation. While existing techniques summarize constraint for entire genes, single gene-wide metrics conceal regional constraint variability within each gene. Therefore, we have created a detailed map of constrained coding regions (CCRs) by leveraging variation observed among 123,136 humans from the Genome Aggregation Database. Read More

Nat Genet 2019 Jan;51(1):7-9

Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.

Nat Genet 2019 Jan;51(1):10-11

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Nat Genet 2019 Jan 3;51(1):76-87. Epub 2018 Dec 3.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0. Read More

Nat Genet 2019 Jan 3;51(1):36-41. Epub 2018 Dec 3.

Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity and DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutation remain unknown. Here, we show that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis. Read More