11 results on '"eQTLGen Consortium"'
Search Results
2. Large-Scale Multi-Omics Studies Provide New Insights into Blood Pressure Regulation
- Author
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Zoha Kamali, Jacob M. Keaton, Shaghayegh Haghjooy Javanmard, International Consortium of Blood Pressure, Million Veteran Program, eQTLGen Consortium, BIOS Consortium, Todd L. Edwards, Harold Snieder, and Ahmad Vaez
- Subjects
blood pressure ,genome ,epigenome ,gene expression ,functional enrichment ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Recent genome-wide association studies uncovered part of blood pressure’s heritability. However, there is still a vast gap between genetics and biology that needs to be bridged. Here, we followed up blood pressure genome-wide summary statistics of over 750,000 individuals, leveraging comprehensive epigenomic and transcriptomic data from blood with a follow-up in cardiovascular tissues to prioritise likely causal genes and underlying blood pressure mechanisms. We first prioritised genes based on coding consequences, multilayer molecular associations, blood pressure-associated expression levels, and coregulation evidence. Next, we followed up the prioritised genes in multilayer studies of genomics, epigenomics, and transcriptomics, functional enrichment, and their potential suitability as drug targets. Our analyses yielded 1880 likely causal genes for blood pressure, tens of which are targets of the available licensed drugs. We identified 34 novel genes for blood pressure, supported by more than one source of biological evidence. Twenty-eight (82%) of these new genes were successfully replicated by transcriptome-wide association analyses in a large independent cohort (n = ~220,000). We also found a substantial mediating role for epigenetic regulation of the prioritised genes. Our results provide new insights into genetic regulation of blood pressure in terms of likely causal genes and involved biological pathways offering opportunities for future translation into clinical practice.
- Published
- 2022
- Full Text
- View/download PDF
3. Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus
- Author
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Mathieson, Iain, Day, Felix R, Barban, Nicola, Tropf, Felix C, Brazel, David M, EQTLGen Consortium, BIOS Consortium, Vaez, Ahmad, Van Zuydam, Natalie, Bitarello, Bárbara D, Gardner, Eugene J, Akimova, Evelina T, Azad, Ajuna, Bergmann, Sven, Bielak, Lawrence F, Boomsma, Dorret I, Bosak, Kristina, Brumat, Marco, Buring, Julie E, Cesarini, David, Chasman, Daniel I, Chavarro, Jorge E, Cocca, Massimiliano, Concas, Maria Pina, Davey Smith, George, Davies, Gail, Deary, Ian J, Esko, Tõnu, Faul, Jessica D, FinnGen Study, Franco, Oscar, Ganna, Andrea, Gaskins, Audrey J, Gelemanovic, Andrea, De Geus, Eco JC, Gieger, Christian, Girotto, Giorgia, Gopinath, Bamini, Grabe, Hans Jörgen, Gunderson, Erica P, Hayward, Caroline, He, Chunyan, Van Heemst, Diana, Hill, W David, Hoffmann, Eva R, Homuth, Georg, Hottenga, Jouke Jan, Huang, Hongyang, Hyppӧnen, Elina, Ikram, M Arfan, Jansen, Rick, Johannesson, Magnus, Kamali, Zoha, Kardia, Sharon LR, Kavousi, Maryam, Kifley, Annette, Kiiskinen, Tuomo, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Liew, Gerald, Lifelines Cohort Study, Lind, Penelope A, Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik KE, Mahajan, Anubha, Martin, Nicholas G, Mbarek, Hamdi, McCarthy, Mark I, McMahon, George, Medland, Sarah E, Meitinger, Thomas, Metspalu, Andres, Mihailov, Evelin, Milani, Lili, Missmer, Stacey A, Mitchell, Paul, Møllegaard, Stine, Mook-Kanamori, Dennis O, Morgan, Anna, Van Der Most, Peter J, De Mutsert, Renée, Nauck, Matthias, Nolte, Ilja M, Noordam, Raymond, Penninx, Brenda WJH, Peters, Annette, Peyser, Patricia A, Polašek, Ozren, Power, Chris, Pribisalic, Ajka, Redmond, Paul, Rich-Edwards, Janet W, Ridker, Paul M, Rietveld, Cornelius A, Ring, Susan M, Rose, Lynda M, Rueedi, Rico, Shukla, Vallari, Smith, Jennifer A, Stankovic, Stasa, Stefánsson, Kári, Stöckl, Doris, Strauch, Konstantin, Swertz, Morris A, Teumer, Alexander, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A Roy, Timpson, Nicholas J, Turman, Constance, Uitterlinden, André G, Waldenberger, Melanie, Wareham, Nicholas J, Weir, David R, Willemsen, Gonneke, Zhao, Jing Hau, Zhao, Wei, Zhao, Yajie, Snieder, Harold, Den Hoed, Marcel, Ong, Ken K, Mills, Melinda C, Perry, John RB, Mathieson, Iain [0000-0002-4256-3982], Day, Felix R [0000-0003-3789-7651], Vaez, Ahmad [0000-0001-9048-3795], Bitarello, Bárbara D [0000-0001-7676-9367], Gardner, Eugene J [0000-0001-9671-1533], Akimova, Evelina T [0000-0001-8733-3745], Bergmann, Sven [0000-0002-6785-9034], Bielak, Lawrence F [0000-0002-3443-8030], Boomsma, Dorret I [0000-0002-7099-7972], Chasman, Daniel I [0000-0003-3357-0862], Chavarro, Jorge E [0000-0002-4436-9630], Cocca, Massimiliano [0000-0002-1127-7596], Concas, Maria Pina [0000-0003-3598-2537], Davey Smith, George [0000-0002-1407-8314], Davies, Gail [0000-0003-1120-7026], Franco, Oscar [0000-0002-4606-4929], Ganna, Andrea [0000-0002-8147-240X], Gaskins, Audrey J [0000-0001-9195-646X], Gieger, Christian [0000-0001-6986-9554], Girotto, Giorgia [0000-0003-4507-6589], Grabe, Hans Jörgen [0000-0003-3684-4208], Gunderson, Erica P [0000-0002-2039-1964], He, Chunyan [0000-0001-9443-4368], Hoffmann, Eva R [0000-0002-2588-0652], Homuth, Georg [0000-0001-6839-0605], Hottenga, Jouke Jan [0000-0002-5668-2368], Hyppӧnen, Elina [0000-0003-3670-9399], Ikram, M Arfan [0000-0003-0372-8585], Jansen, Rick [0000-0002-3333-6737], Johannesson, Magnus [0000-0001-8759-6393], Kamali, Zoha [0000-0001-6492-5887], Kavousi, Maryam [0000-0001-5976-6519], Kifley, Annette [0000-0002-3764-4905], Kiiskinen, Tuomo [0000-0002-6306-8227], Kraft, Peter [0000-0002-4472-8103], Langenberg, Claudia [0000-0002-5017-7344], Lind, Penelope A [0000-0002-3887-2598], Luan, Jian'an [0000-0003-3137-6337], Magnusson, Patrik KE [0000-0002-7315-7899], Mahajan, Anubha [0000-0001-5585-3420], Mbarek, Hamdi [0000-0002-1108-0371], Metspalu, Andres [0000-0002-3718-796X], Milani, Lili [0000-0002-5323-3102], Møllegaard, Stine [0000-0001-5676-2248], Morgan, Anna [0000-0001-6290-445X], van der Most, Peter J [0000-0001-8450-3518], Nauck, Matthias [0000-0002-6678-7964], Nolte, Ilja M [0000-0001-5047-4077], Noordam, Raymond [0000-0001-7801-809X], Peters, Annette [0000-0001-6645-0985], Peyser, Patricia A [0000-0002-9717-8459], Pribisalic, Ajka [0000-0002-3725-3728], Rietveld, Cornelius A [0000-0003-4053-1861], Ring, Susan M [0000-0003-3103-9330], Smith, Jennifer A [0000-0002-3575-5468], Stankovic, Stasa [0000-0002-6602-1379], Teumer, Alexander [0000-0002-8309-094X], Thurik, A Roy [0000-0002-0242-6908], Timpson, Nicholas J [0000-0002-7141-9189], Uitterlinden, André G [0000-0002-7276-3387], Waldenberger, Melanie [0000-0003-0583-5093], Wareham, Nicholas J [0000-0003-1422-2993], Weir, David R [0000-0002-1661-2402], Zhao, Wei [0000-0001-7388-0692], Zhao, Yajie [0000-0002-2747-0219], Snieder, Harold [0000-0003-1949-2298], den Hoed, Marcel [0000-0001-8081-428X], Ong, Ken K [0000-0003-4689-7530], Mills, Melinda C [0000-0003-1704-0001], Perry, John RB [0000-0001-6483-3771], and Apollo - University of Cambridge Repository
- Subjects
Aging ,Fertility ,Reproduction ,Humans ,Female ,Menopause ,Selection, Genetic ,FOS: Medical biotechnology ,Child - Abstract
Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.
- Published
- 2023
4. Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure
- Author
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Oelen, Roy, de Vries, Dylan H, Brugge, Harm, Gordon, M Grace, Vochteloo, Martijn, single-cell eQTLGen consortium, BIOS Consortium, Ye, Chun J, Westra, Harm-Jan, Franke, Lude, and van der Wijst, Monique GP
- Subjects
Lupus Erythematosus ,C-Type ,Mitogen ,Inflammatory and immune system ,Mononuclear ,Systemic ,Human Genome ,Gene Expression Regulation ,Lectins ,Receptors ,Leukocytes ,Genetics ,Humans ,RNA ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,BIOS Consortium ,Aetiology ,single-cell eQTLGen consortium ,Infection ,Signal Transduction ,Biotechnology - Abstract
The host's gene expression and gene regulatory response to pathogen exposure can be influenced by a combination of the host's genetic background, the type of and exposure time to pathogens. Here we provide a detailed dissection of this using single-cell RNA-sequencing of 1.3M peripheral blood mononuclear cells from 120 individuals, longitudinally exposed to three different pathogens. These analyses indicate that cell-type-specificity is a more prominent factor than pathogen-specificity regarding contexts that affect how genetics influences gene expression (i.e., eQTL) and co-expression (i.e., co-expression QTL). In monocytes, the strongest responder to pathogen stimulations, 71.4% of the genetic variants whose effect on gene expression is influenced by pathogen exposure (i.e., response QTL) also affect the co-expression between genes. This indicates widespread, context-specific changes in gene expression level and its regulation that are driven by genetics. Pathway analysis on the CLEC12A gene that exemplifies cell-type-, exposure-time- and genetic-background-dependent co-expression interactions, shows enrichment of the interferon (IFN) pathway specifically at 3-h post-exposure in monocytes. Similar genetic background-dependent association between IFN activity and CLEC12A co-expression patterns is confirmed in systemic lupus erythematosus by in silico analysis, which implies that CLEC12A might be an IFN-regulated gene. Altogether, this study highlights the importance of context for gaining a better understanding of the mechanisms of gene regulation in health and disease.
- Published
- 2022
5. OTTERS: a powerful TWAS framework leveraging summary-level reference data.
- Author
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Dai, Qile, Zhou, Geyu, Zhao, Hongyu, Võsa, Urmo, Franke, Lude, Battle, Alexis, Teumer, Alexander, Lehtimäki, Terho, Raitakari, Olli T., Esko, Tõnu, eQTLGen Consortium, Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand Kumar, Arindrarto, Wibowo, Awadalla, Philip, Beutner, Frank, Jan Bonder, Marc, and Boomsma, Dorret I.
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DISEASE risk factors ,MONOGENIC & polygenic inheritance (Genetics) ,OTTERS ,SAMPLE size (Statistics) - Abstract
Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies. Here, the authors present a TWAS framework OTTERS that adapts multiple polygenic risk score methods to estimate eQTL weights from summary-level eQTL data. Both simulation and real studies show OTTERS is powerful across a wide range of genetic architectures. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour
- Author
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Mills, Melinda C, Tropf, Felix C, Brazel, David M, van Zuydam, Natalie, Vaez, Ahmad, eQTLGen Consortium, BIOS Consortium, Human Reproductive Behaviour Consortium, Pers, Tune H, Snieder, Harold, Perry, John RB, Ong, Ken K, den Hoed, Marcel, Barban, Nicola, Day, Felix R, Mills, Melinda C [0000-0003-1704-0001], Tropf, Felix C [0000-0003-2445-515X], Brazel, David M [0000-0001-5361-2498], Vaez, Ahmad [0000-0001-9048-3795], Pers, Tune H [0000-0003-0207-4831], Snieder, Harold [0000-0003-1949-2298], Perry, John RB [0000-0001-6483-3771], Ong, Ken K [0000-0003-4689-7530], den Hoed, Marcel [0000-0001-8081-428X], Barban, Nicola [0000-0002-4362-4652], Day, Felix R [0000-0003-3789-7651], and Apollo - University of Cambridge Repository
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Male ,Adolescent ,Reproduction ,Age Factors ,Coitus ,Parturition ,Humans ,Female ,Polymorphism, Single Nucleotide ,Genetic Association Studies - Abstract
Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.
- Published
- 2021
7. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour.
- Author
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Mills, Melinda C., Tropf, Felix C., Brazel, David M., van Zuydam, Natalie, Vaez, Ahmad, eQTLGen Consortium, Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand Kumar, Arindrarto, Wibowo, Awadalla, Philip, Battle, Alexis, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark W., Claringbould, Annique, Deelen, Patrick, and Esko, Tõnu
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- 2021
- Full Text
- View/download PDF
8. Demuxafy: improvement in droplet assignment by integrating multiple single-cell demultiplexing and doublet detection methods
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Drew Neavin, Anne Senabouth, Himanshi Arora, Jimmy Tsz Hang Lee, Aida Ripoll-Cladellas, sc-eQTLGen Consortium, Lude Franke, Shyam Prabhakar, Chun Jimmie Ye, Davis J. McCarthy, Marta Melé, Martin Hemberg, and Joseph E. Powell
- Subjects
Single-cell analysis ,Genetic demultiplexing ,Doublet detecting ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Recent innovations in single-cell RNA-sequencing (scRNA-seq) provide the technology to investigate biological questions at cellular resolution. Pooling cells from multiple individuals has become a common strategy, and droplets can subsequently be assigned to a specific individual by leveraging their inherent genetic differences. An implicit challenge with scRNA-seq is the occurrence of doublets—droplets containing two or more cells. We develop Demuxafy, a framework to enhance donor assignment and doublet removal through the consensus intersection of multiple demultiplexing and doublet detecting methods. Demuxafy significantly improves droplet assignment by separating singlets from doublets and classifying the correct individual.
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- 2024
- Full Text
- View/download PDF
9. Identification of genetic variants that impact gene co-expression relationships using large-scale single-cell data
- Author
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Shuang Li, Katharina T. Schmid, Dylan H. de Vries, Maryna Korshevniuk, Corinna Losert, Roy Oelen, Irene V. van Blokland, BIOS Consortium, sc-eQTLgen Consortium, Hilde E. Groot, Morris A. Swertz, Pim van der Harst, Harm-Jan Westra, Monique G.P. van der Wijst, Matthias Heinig, and Lude Franke
- Subjects
Co-expression QTLs ,scRNA-seq ,eQTL ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Background Expression quantitative trait loci (eQTL) studies show how genetic variants affect downstream gene expression. Single-cell data allows reconstruction of personalized co-expression networks and therefore the identification of SNPs altering co-expression patterns (co-expression QTLs, co-eQTLs) and the affected upstream regulatory processes using a limited number of individuals. Results We conduct a co-eQTL meta-analysis across four scRNA-seq peripheral blood mononuclear cell datasets using a novel filtering strategy followed by a permutation-based multiple testing approach. Before the analysis, we evaluate the co-expression patterns required for co-eQTL identification using different external resources. We identify a robust set of cell-type-specific co-eQTLs for 72 independent SNPs affecting 946 gene pairs. These co-eQTLs are replicated in a large bulk cohort and provide novel insights into how disease-associated variants alter regulatory networks. One co-eQTL SNP, rs1131017, that is associated with several autoimmune diseases, affects the co-expression of RPS26 with other ribosomal genes. Interestingly, specifically in T cells, the SNP additionally affects co-expression of RPS26 and a group of genes associated with T cell activation and autoimmune disease. Among these genes, we identify enrichment for targets of five T-cell-activation-related transcription factors whose binding sites harbor rs1131017. This reveals a previously overlooked process and pinpoints potential regulators that could explain the association of rs1131017 with autoimmune diseases. Conclusion Our co-eQTL results highlight the importance of studying context-specific gene regulation to understand the biological implications of genetic variation. With the expected growth of sc-eQTL datasets, our strategy and technical guidelines will facilitate future co-eQTL identification, further elucidating unknown disease mechanisms.
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- 2023
- Full Text
- View/download PDF
10. Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure
- Author
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Roy Oelen, Dylan H. de Vries, Harm Brugge, M. Grace Gordon, Martijn Vochteloo, single-cell eQTLGen consortium, BIOS Consortium, Chun J. Ye, Harm-Jan Westra, Lude Franke, and Monique G. P. van der Wijst
- Subjects
Science - Abstract
Not just differential gene expression but also differential gene regulation in immune cells account for individual differences in the immune response. Authors show here by single-cell RNA-sequencing of peripheral blood mononuclear cells from a large cohort of genetically diverse individuals that gene expression and regulatory changes in these cells depend on the context of and interactions between cell types, genetics, type of pathogen and time after exposure.
- Published
- 2022
- Full Text
- View/download PDF
11. Large-Scale Multi-Omics Studies Provide New Insights into Blood Pressure Regulation.
- Author
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Kamali Z, Keaton JM, Haghjooy Javanmard S, International Consortium Of Blood Pressure, Million Veteran Program, eQTLGen Consortium, Bios Consortium, Edwards TL, Snieder H, and Vaez A
- Subjects
- Blood Pressure genetics, Epigenomics methods, Genomics methods, Humans, Transcriptome, Epigenesis, Genetic, Genome-Wide Association Study
- Abstract
Recent genome-wide association studies uncovered part of blood pressure's heritability. However, there is still a vast gap between genetics and biology that needs to be bridged. Here, we followed up blood pressure genome-wide summary statistics of over 750,000 individuals, leveraging comprehensive epigenomic and transcriptomic data from blood with a follow-up in cardiovascular tissues to prioritise likely causal genes and underlying blood pressure mechanisms. We first prioritised genes based on coding consequences, multilayer molecular associations, blood pressure-associated expression levels, and coregulation evidence. Next, we followed up the prioritised genes in multilayer studies of genomics, epigenomics, and transcriptomics, functional enrichment, and their potential suitability as drug targets. Our analyses yielded 1880 likely causal genes for blood pressure, tens of which are targets of the available licensed drugs. We identified 34 novel genes for blood pressure, supported by more than one source of biological evidence. Twenty-eight (82%) of these new genes were successfully replicated by transcriptome-wide association analyses in a large independent cohort ( n = ~220,000). We also found a substantial mediating role for epigenetic regulation of the prioritised genes. Our results provide new insights into genetic regulation of blood pressure in terms of likely causal genes and involved biological pathways offering opportunities for future translation into clinical practice.
- Published
- 2022
- Full Text
- View/download PDF
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