RESUMEN
Gene promoter and enhancer sequences are bound by transcription factors and are depleted of methylated CpG sites (cytosines preceding guanines in DNA). The absence of methylated CpGs in these sequences typically correlates with increased gene expression, indicating a regulatory role for methylation. We used nanopore sequencing to determine haplotype-specific methylation rates of 15.3 million CpG units in 7,179 whole-blood genomes. We identified 189,178 methylation depleted sequences where three or more proximal CpGs were unmethylated on at least one haplotype. A total of 77,789 methylation depleted sequences (~41%) associated with 80,503 cis-acting sequence variants, which we termed allele-specific methylation quantitative trait loci (ASM-QTLs). RNA sequencing of 896 samples from the same blood draws used to perform nanopore sequencing showed that the ASM-QTL, that is, DNA sequence variability, drives most of the correlation found between gene expression and CpG methylation. ASM-QTLs were enriched 40.2-fold (95% confidence interval 32.2, 49.9) among sequence variants associating with hematological traits, demonstrating that ASM-QTLs are important functional units in the noncoding genome.
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Islas de CpG , Metilación de ADN , Sitios de Carácter Cuantitativo , Humanos , Regiones Promotoras Genéticas , Haplotipos , Alelos , Regulación de la Expresión Génica , Variación Genética , Secuenciación de Nanoporos/métodos , Genoma HumanoRESUMEN
BACKGROUND: Long-read sequencing can enable the detection of base modifications, such as CpG methylation, in single molecules of DNA. The most commonly used methods for long-read sequencing are nanopore developed by Oxford Nanopore Technologies (ONT) and single molecule real-time (SMRT) sequencing developed by Pacific Bioscience (PacBio). In this study, we systematically compare the performance of CpG methylation detection from long-read sequencing. RESULTS: We demonstrate that CpG methylation detection from 7179 nanopore-sequenced DNA samples is highly accurate and consistent with 132 oxidative bisulfite-sequenced (oxBS) samples, isolated from the same blood draws. We introduce quality filters for CpGs that further enhance the accuracy of CpG methylation detection from nanopore-sequenced DNA, while removing at most 30% of CpGs. We evaluate the per-site performance of CpG methylation detection across different genomic features and CpG methylation rates and demonstrate how the latest R10.4 flowcell chemistry and base-calling algorithms improve methylation detection from nanopore sequencing. Additionally, we show how the methylation detection of 50 SMRT-sequenced genomes compares to nanopore sequencing and oxBS. CONCLUSIONS: This study provides the first systematic comparison of CpG methylation detection tools for long-read sequencing methods. We compare two commonly used computational methods for the detection of CpG methylation in a large number of nanopore genomes, including samples sequenced using the latest R10.4 nanopore flowcell chemistry and 50 SMRT sequenced samples. We provide insights into the strengths and limitations of each sequencing method as well as recommendations for standardization and evaluation of tools designed for genome-scale modified base detection using long-read sequencing.
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Metilación de ADN , Genoma Humano , Humanos , Análisis de Secuencia de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , ADNRESUMEN
BACKGROUND: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking. METHODS: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers. RESULTS: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span. CONCLUSIONS: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).
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Enfermedad , Genómica , Longevidad , Humanos , Alelos , Pruebas Genéticas , Variación Genética , Genotipo , Islandia/epidemiología , Longevidad/genética , Enfermedad/genética , Enfermedades Cardiovasculares/genética , Neoplasias/genéticaRESUMEN
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A.
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Hematopoyesis Clonal , Estudio de Asociación del Genoma Completo , Humanos , Anciano , Hematopoyesis Clonal/genética , Hematopoyesis/genética , Mutación/genética , Células Madre Hematopoyéticas/metabolismoRESUMEN
High-throughput proteomics platforms measuring thousands of proteins in plasma combined with genomic and phenotypic information have the power to bridge the gap between the genome and diseases. Here we performed association studies of Olink Explore 3072 data generated by the UK Biobank Pharma Proteomics Project1 on plasma samples from more than 50,000 UK Biobank participants with phenotypic and genotypic data, stratifying on British or Irish, African and South Asian ancestries. We compared the results with those of a SomaScan v4 study on plasma from 36,000 Icelandic people2, for 1,514 of whom Olink data were also available. We found modest correlation between the two platforms. Although cis protein quantitative trait loci were detected for a similar absolute number of assays on the two platforms (2,101 on Olink versus 2,120 on SomaScan), the proportion of assays with such supporting evidence for assay performance was higher on the Olink platform (72% versus 43%). A considerable number of proteins had genomic associations that differed between the platforms. We provide examples where differences between platforms may influence conclusions drawn from the integration of protein levels with the study of diseases. We demonstrate how leveraging the diverse ancestries of participants in the UK Biobank helps to detect novel associations and refine genomic location. Our results show the value of the information provided by the two most commonly used high-throughput proteomics platforms and demonstrate the differences between them that at times provides useful complementarity.
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Proteínas Sanguíneas , Susceptibilidad a Enfermedades , Genómica , Genotipo , Fenotipo , Proteómica , Humanos , África/etnología , Sur de Asia/etnología , Bancos de Muestras Biológicas , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/genética , Conjuntos de Datos como Asunto , Genoma Humano/genética , Islandia/etnología , Irlanda/etnología , Plasma/química , Proteoma/análisis , Proteoma/genética , Proteómica/métodos , Sitios de Carácter Cuantitativo , Reino UnidoRESUMEN
Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.
Asunto(s)
Epilepsia , Trastornos Migrañosos , Migraña con Aura , Humanos , Estudio de Asociación del Genoma Completo , Trastornos Migrañosos/genética , Migraña con Aura/genética , FenotipoRESUMEN
Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data1,2. Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank3. This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation.
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Bancos de Muestras Biológicas , Bases de Datos Genéticas , Variación Genética , Genoma Humano , Genómica , Secuenciación Completa del Genoma , África/etnología , Asia/etnología , Estudios de Cohortes , Secuencia Conservada , Exones/genética , Genoma Humano/genética , Haplotipos/genética , Humanos , Mutación INDEL , Irlanda/etnología , Repeticiones de Microsatélite , Polimorfismo de Nucleótido Simple/genética , Reino UnidoRESUMEN
Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.
Asunto(s)
Degeneración del Disco Intervertebral/genética , Desplazamiento del Disco Intervertebral/genética , Disco Intervertebral/metabolismo , Cotransportador de Sodio-Sulfato/genética , Cotransportador de Sodio-Sulfato/metabolismo , Sulfatos/metabolismo , Regiones no Traducidas 3' , Huesos/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Simportadores/genética , Simportadores/metabolismoRESUMEN
The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF) < 1%). We tested plasma protein levels for association with 373 diseases and other traits and identified 257,490 associations. We integrated pQTL and genetic associations with diseases and other traits and found that 12% of 45,334 lead associations in the GWAS Catalog are with variants in high linkage disequilibrium with pQTL. We identified 938 genes encoding potential drug targets with variants that influence levels of possible biomarkers. Combining proteomics, genomics and transcriptomics, we provide a valuable resource that can be used to improve understanding of disease pathogenesis and to assist with drug discovery and development.
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Proteínas Sanguíneas/genética , Enfermedad/genética , Proteoma/genética , Biomarcadores/sangre , Proteínas Sanguíneas/metabolismo , Femenino , Frecuencia de los Genes , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Sitios de Carácter CuantitativoRESUMEN
The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in PTPN14 conferred substantial risks of BCC (OR, 8.0; P = 1.9 × 10-12), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the PTPN14 locus were associated with BCC, suggesting PTPN14 as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, P = 1.6 × 10-4) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis. SIGNIFICANCE: This study identifies the tumor-suppressor gene PTPN14 as a high-impact BCC predisposition gene and indicates that inactivation of PTPN14 by germline sequence variants may also lead to increased risk of cervical cancer.
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Carcinoma Basocelular/genética , Mutación con Pérdida de Función , Penetrancia , Proteínas Tirosina Fosfatasas no Receptoras/genética , Neoplasias Cutáneas/genética , Neoplasias del Cuello Uterino/genética , Factores de Edad , Carcinoma Basocelular/epidemiología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genes Supresores de Tumor , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Estudio de Asociación del Genoma Completo , Genotipo , Mutación de Línea Germinal , Humanos , Islandia/epidemiología , Masculino , Oportunidad Relativa , Neoplasias Cutáneas/epidemiología , Bancos de Tejidos/estadística & datos numéricos , Reino Unido/epidemiología , Neoplasias del Cuello Uterino/epidemiología , Secuenciación del Exoma/estadística & datos numéricos , Secuenciación Completa del Genoma/estadística & datos numéricosRESUMEN
Despite the important role that monozygotic twins have played in genetics research, little is known about their genomic differences. Here we show that monozygotic twins differ on average by 5.2 early developmental mutations and that approximately 15% of monozygotic twins have a substantial number of these early developmental mutations specific to one of them. Using the parents and offspring of twins, we identified pre-twinning mutations. We observed instances where a twin was formed from a single cell lineage in the pre-twinning cell mass and instances where a twin was formed from several cell lineages. CpG>TpG mutations increased in frequency with embryonic development, coinciding with an increase in DNA methylation. Our results indicate that allocations of cells during development shapes genomic differences between monozygotic twins.
Asunto(s)
Genoma Humano , Células Germinativas/metabolismo , Gemelos Monocigóticos/genética , Desarrollo Embrionario/genética , Femenino , Frecuencia de los Genes/genética , Humanos , Masculino , Mosaicismo , Mutación/genética , Cigoto/metabolismoRESUMEN
PURPOSE: The aim of Copenhagen Hospital Biobank-Cardiovascular Disease Cohort (CHB-CVDC) is to establish a cohort that can accelerate our understanding of CVD initiation and progression by jointly studying genetics, diagnoses, treatments and risk factors. PARTICIPANTS: The CHB-CVDC is a large genomic cohort of patients with CVD. CHB-CVDC currently includes 96 308 patients. The cohort is part of CHB initiated in 2009 in the Capital Region of Denmark. CHB is continuously growing with ~40 000 samples/year. Patients in CHB were included in CHB-CVDC if they were above 18 years of age and assigned at least one cardiovascular diagnosis. Additionally, up-to 110 000 blood donors can be analysed jointly with CHB-CVDC. Linkage with the Danish National Health Registries, Electronic Patient Records, and Clinical Quality Databases allow up-to 41 years of medical history. All individuals are genotyped using the Infinium Global Screening Array from Illumina and imputed using a reference panel consisting of whole-genome sequence data from 8429 Danes along with 7146 samples from North-Western Europe. Currently, 39 539 of the patients are deceased. FINDINGS TO DATE: Here, we demonstrate the utility of the cohort by showing concordant effects between known variants and selected CVDs, that is, >93% concordance for coronary artery disease, atrial fibrillation, heart failure and cholesterol measurements and 85% concordance for hypertension. Furthermore, we evaluated multiple study designs and the validity of using Danish blood donors as part of CHB-CVDC. Lastly, CHB-CVDC has already made major contributions to studies of sick sinus syndrome and the role of phytosterols in development of atherosclerosis. FUTURE PLANS: In addition to genetics, electronic patient records, national socioeconomic and health registries extensively characterise each patient in CHB-CVDC and provides a promising framework for improved understanding of risk and protective variants. We aim to include other measurable biomarkers for example, proteins in CHB-CVDC making it a platform for multiomics cardiovascular studies.
Asunto(s)
Enfermedades Cardiovasculares , Cardiopatías , Bancos de Muestras Biológicas , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Estudios de Cohortes , Hospitales , HumanosRESUMEN
Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (EffectCys506Ser = -1.61 SD, CI95 = [-1.98, -1.35]; EffectLys334Ter = 0.63 SD, CI95 = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10-14). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.
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Eritropoyesis/genética , Mutación con Ganancia de Función , Hemoglobinas/metabolismo , Proteína 1 Reguladora de Hierro/genética , Mutación con Pérdida de Función , Biomarcadores/sangre , Bases de Datos Genéticas , Estudio de Asociación del Genoma Completo , Humanos , Islandia , Proteína 1 Reguladora de Hierro/metabolismo , Reino UnidoRESUMEN
Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
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Deleción Cromosómica , Cromosomas Humanos Y/genética , Predisposición Genética a la Enfermedad/genética , Inestabilidad Genómica/genética , Leucocitos/patología , Mosaicismo , Adulto , Anciano , Biología Computacional , Bases de Datos Genéticas , Femenino , Marcadores Genéticos/genética , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/genética , Reino UnidoRESUMEN
Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 - 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10-42, ß = -0.090) and confers risk of hip fracture (P = 1.0 × 10-8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density.
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Densidad Ósea/genética , Fracturas de Cadera/genética , MicroARNs/genética , Osteoartritis/genética , Absorciometría de Fotón , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estatura/genética , Huesos/diagnóstico por imagen , Huesos/fisiología , Estudios de Casos y Controles , Colágeno Tipo XI/genética , Femenino , Estudios de Seguimiento , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Factor 5 de Diferenciación de Crecimiento/genética , Fracturas de Cadera/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis/epidemiología , Factores de RiesgoRESUMEN
The original HTML version of this Article was updated shortly after publication to add links to the Peer Review file.In addition, affiliations 16 and 17 incorrectly read 'School of Medicine Sydney, University of Notre Dame Australia, Sydney, WA, 6160, Australia' and 'St Vincent's Clinical School, University of New South Wales Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.' This has now been corrected in both the PDF and HTML versions of the Article.
RESUMEN
Genetic diversity arises from recombination and de novo mutation (DNM). Using a combination of microarray genotype and whole-genome sequence data on parent-child pairs, we identified 4,531,535 crossover recombinations and 200,435 DNMs. The resulting genetic map has a resolution of 682 base pairs. Crossovers exhibit a mutagenic effect, with overrepresentation of DNMs within 1 kilobase of crossovers in males and females. In females, a higher mutation rate is observed up to 40 kilobases from crossovers, particularly for complex crossovers, which increase with maternal age. We identified 35 loci associated with the recombination rate or the location of crossovers, demonstrating extensive genetic control of meiotic recombination, and our results highlight genes linked to the formation of the synaptonemal complex as determinants of crossovers.
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Intercambio Genético , Análisis Mutacional de ADN , Tasa de Mutación , Mapeo Cromosómico , Epigénesis Genética , Femenino , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Humanos , Islandia , Masculino , Edad Materna , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Complejo SinaptonémicoRESUMEN
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. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10-27, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10-8, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.