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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
Urticaria is a skin disorder characterized by outbreaks of raised pruritic wheals. In order to identify sequence variants associated with urticaria, we performed a meta-analysis of genome-wide association studies for urticaria with a total of 40,694 cases and 1,230,001 controls from Iceland, the UK, Finland, and Japan. We also performed transcriptome- and proteome-wide analyses in Iceland and the UK. We found nine sequence variants at nine loci associating with urticaria. The variants are at genes participating in type 2 immune responses and/or mast cell biology (CBLB, FCER1A, GCSAML, STAT6, TPSD1, ZFPM1), the innate immunity (C4), and NF-κB signaling. The most significant association was observed for the splice-donor variant rs56043070[A] (hg38: chr1:247556467) in GCSAML (MAF = 6.6%, OR = 1.24 (95%CI: 1.20-1.28), P-value = 3.6 × 10-44). We assessed the effects of the variants on transcripts, and levels of proteins relevant to urticaria pathophysiology. Our results emphasize the role of type 2 immune response and mast cell activation in the pathogenesis of urticaria. Our findings may point to an IgE-independent urticaria pathway that could help address unmet clinical need.
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Estudio de Asociación del Genoma Completo , Urticaria , Humanos , Mastocitos , Urticaria/genética , Empalme del ARN , ProteomaRESUMEN
Superconducting qubits seem promising for useful quantum computers, but the currently wide-spread qubit designs and techniques do not yet provide high enough performance. Here, we introduce a superconducting-qubit type, the unimon, which combines the desired properties of increased anharmonicity, full insensitivity to dc charge noise, reduced sensitivity to flux noise, and a simple structure consisting only of a single Josephson junction in a resonator. In agreement with our quantum models, we measure the qubit frequency, ω01/(2π), and increased anharmonicity α/(2π) at the optimal operation point, yielding, for example, 99.9% and 99.8% fidelity for 13 ns single-qubit gates on two qubits with (ω01, α) = (4.49 GHz, 434 MHz) × 2π and (3.55 GHz, 744 MHz) × 2π, respectively. The energy relaxation seems to be dominated by dielectric losses. Thus, improvements of the design, materials, and gate time may promote the unimon to break the 99.99% fidelity target for efficient quantum error correction and possible useful quantum advantage with noisy systems.
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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
Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.
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Anemia Ferropénica/genética , Sitios Genéticos , Variación Genética , Sobrecarga de Hierro/genética , Hierro/sangre , Anemia Ferropénica/sangre , Anemia Ferropénica/diagnóstico , Biomarcadores/sangre , Dinamarca , Ferritinas/sangre , Estudio de Asociación del Genoma Completo , Genotipo , Homeostasis , Humanos , Islandia , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/diagnóstico , Fenotipo , Medición de Riesgo , Factores de Riesgo , Transferrina/metabolismo , 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.
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Osteoarthritis has a highly negative impact on quality of life because of the associated pain and loss of joint function. Here we describe the largest meta-analysis so far of osteoarthritis of the hip and the knee in samples from Iceland and the UK Biobank (including 17,151 hip osteoarthritis patients, 23,877 knee osteoarthritis patients, and more than 562,000 controls). We found 23 independent associations at 22 loci in the additive meta-analyses, of which 16 of the loci were novel: 12 for hip and 4 for knee osteoarthritis. Two associations are between rare or low-frequency missense variants and hip osteoarthritis, affecting the genes SMO (rs143083812, frequency 0.11%, odds ratio (OR) = 2.8, P = 7.9 × 10-12, p.Arg173Cys) and IL11 (rs4252548, frequency 2.08%, OR = 1.30, P = 2.1 × 10-11, p.Arg112His). A common missense variant in the COL11A1 gene also associates with hip osteoarthritis (rs3753841, frequency 61%, P = 5.2 × 10-10, OR = 1.08, p.Pro1284Leu). In addition, using a recessive model, we confirm an association between hip osteoarthritis and a variant of CHADL1 (rs117018441, P = 1.8 × 10-25, OR = 5.9). Furthermore, we observe a complex relationship between height and risk of osteoarthritis.
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Colágeno Tipo XI/genética , Sitios Genéticos , Interleucina-11/genética , Mutación Missense , Osteoartritis/genética , Receptor Smoothened/genética , Adulto , Anciano , Estudios de Casos y Controles , Conjuntos de Datos como Asunto/estadística & datos numéricos , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Islandia/epidemiología , Masculino , Persona de Mediana Edad , Osteoartritis/epidemiología , Polimorfismo de Nucleótido Simple , Reino Unido/epidemiologíaRESUMEN
Classical realism demands that system properties exist independently of whether they are measured, while noncontextuality demands that the results of measurements do not depend on what other measurements are performed in conjunction with them. The Bell-Kochen-Specker theorem states that noncontextual realism cannot reproduce the measurement statistics of a single three-level quantum system (qutrit). Noncontextual realistic models may thus be tested using a single qutrit without relying on the notion of quantum entanglement in contrast to Bell inequality tests. It is challenging to refute such models experimentally, since imperfections may introduce loopholes that enable a realist interpretation. Here we use a superconducting qutrit with deterministic, binary-outcome readouts to violate a noncontextuality inequality while addressing the detection, individual-existence and compatibility loopholes. This evidence of state-dependent contextuality also demonstrates the fitness of superconducting quantum circuits for fault-tolerant quantum computation in surface-code architectures, currently the most promising route to scalable quantum computing.