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28 results on '"Almlöf, Jonas Carlsson"'

1. Transancestral mapping and genetic load in systemic lupus erythematosus.

Author

Langefeld, Carl D, Ainsworth, Hannah C, Cunninghame Graham, Deborah S, Kelly, Jennifer A, Comeau, Mary E, Marion, Miranda C, Howard, Timothy D, Ramos, Paula S, Croker, Jennifer A, Morris, David L, Sandling, Johanna K, Almlöf, Jonas Carlsson, Acevedo-Vásquez, Eduardo M, Alarcón, Graciela S, Babini, Alejandra M, Baca, Vicente, Bengtsson, Anders A, Berbotto, Guillermo A, Bijl, Marc, Brown, Elizabeth E, Brunner, Hermine I, Cardiel, Mario H, Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M, Dahlqvist, Solbritt Rantapää, D'Alfonso, Sandra, Da Silva, Berta Martins, de la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C, Endreffy, Emőke, Esquivel-Valerio, Jorge A, Fortin, Paul R, Freedman, Barry I, Frostegård, Johan, García, Mercedes A, de la Torre, Ignacio García, Gilkeson, Gary S, Gladman, Dafna D, Gunnarsson, Iva, Guthridge, Joel M, Huggins, Jennifer L, James, Judith A, Kallenberg, Cees GM, Kamen, Diane L, Karp, David R, Kaufman, Kenneth M, Kottyan, Leah C, Kovács, László, Laustrup, Helle, Lauwerys, Bernard R, Li, Quan-Zhen, Maradiaga-Ceceña, Marco A, Martín, Javier, McCune, Joseph M, McWilliams, David R, Merrill, Joan T, Miranda, Pedro, Moctezuma, José F, Nath, Swapan K, Niewold, Timothy B, Orozco, Lorena, Ortego-Centeno, Norberto, Petri, Michelle, Pineau, Christian A, Pons-Estel, Bernardo A, Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D, Russell, Laurie P, Sabio, José M, Aguilar-Salinas, Carlos A, Scherbarth, Hugo R, Scorza, Raffaella, Seldin, Michael F, Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D, Toloza, Sergio MA, Truedsson, Lennart, Tusié-Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M, Wallace, Daniel J, Weisman, Michael H, Wither, Joan E, Bhangale, Tushar, Oksenberg, Jorge R, Rioux, John D, Gregersen, Peter K, Syvänen, Ann-Christine, Rönnblom, Lars, Criswell, Lindsey A, Jacob, Chaim O, Sivils, Kathy L, Tsao, Betty P, Schanberg, Laura E, and Behrens, Timothy W

Subjects
Humans, Lupus Erythematosus, Systemic, HLA Antigens, Logistic Models, Case-Control Studies, Mutagenesis, Insertional, Age of Onset, Sequence Deletion, Genetic Load, Multifactorial Inheritance, Polymorphism, Single Nucleotide, African Continental Ancestry Group, American Native Continental Ancestry Group, European Continental Ancestry Group, Hispanic Americans, Lupus Erythematosus, Systemic, Mutagenesis, Insertional, Polymorphism, Single Nucleotide
Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P

Published
2017

2. Variants in BANK1 are associated with lupus nephritis of European ancestry

Author

Bolin, Karin, Imgenberg-Kreuz, Juliana, Leonard, Dag, Sandling, Johanna K., Alexsson, Andrei, Pucholt, Pascal, Haarhaus, Malena Loberg, Almlöf, Jonas Carlsson, Nititham, Joanne, Jönsen, Andreas, Sjöwall, Christopher, Bengtsson, Anders A., Rantapää-Dahlqvist, Solbritt, Svenungsson, Elisabet, Gunnarsson, Iva, Syvänen, Ann-Christine, Lerang, Karoline, Troldborg, Anne, Voss, Anne, Molberg, Øyvind, Jacobsen, Søren, Criswell, Lindsey, Rönnblom, Lars, and Nordmark, Gunnel

Published
2021
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6. Contributions of de novo variants to systemic lupus erythematosus

Author

Almlöf, Jonas Carlsson, primary, Nystedt, Sara, additional, Mechtidou, Aikaterini, additional, Leonard, Dag, additional, Eloranta, Maija-Leena, additional, Grosso, Giorgia, additional, Sjöwall, Christopher, additional, Bengtsson, Anders A., additional, Jönsen, Andreas, additional, Gunnarsson, Iva, additional, Svenungsson, Elisabet, additional, Rönnblom, Lars, additional, Sandling, Johanna K., additional, and Syvänen, Ann-Christine, additional

Published
2020
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7. Shared and Unique Patterns of DNA Methylation in Systemic Lupus Erythematosus and Primary Sjogrens Syndrome

Author

Imgenberg-Kreuz, Juliana, Carlsson Almlöf, Jonas Carlsson, Leonard, Dag, Sjöwall, Christopher, Syvanen, Ann-Christine, Ronnblom, Lars, Sandling, Johanna K., Nordmark, Gunnel, Imgenberg-Kreuz, Juliana, Carlsson Almlöf, Jonas Carlsson, Leonard, Dag, Sjöwall, Christopher, Syvanen, Ann-Christine, Ronnblom, Lars, Sandling, Johanna K., and Nordmark, Gunnel

Abstract

Objectives: To performa cross-comparative analysis of DNA methylation in patients with systemic lupus erythematosus (SLE), patients with primary Sjogrens syndrome (pSS), and healthy controls addressing the question of epigenetic sharing and aiming to detect disease-specific alterations. Methods: DNA extracted from peripheral blood from 347 cases with SLE, 100 cases with pSS, and 400 healthy controls were analyzed on the Human Methylation 450k array, targeting 485,000 CpG sites across the genome. A linear regression model including age, sex, and blood cell type distribution as covariates was fitted, and association p-values were Bonferroni corrected. A random forest machine learning classifier was designed for prediction of disease status based on DNA methylation data. Results: We established a combined set of 4,945 shared differentially methylated CpG sites (DMCs) in SLE and pSS compared to controls. In pSS, hypomethylation at type I interferon induced genes was mainly driven by patients who were positive for Ro/SSA and/or La/SSB autoantibodies. Analysis of differential methylation between SLE and pSS identified 2,244 DMCs with a majority of sites showing decreased methylation in SLE compared to pSS. The random forest classifier demonstrated good performance in discerning between disease status with an area under the curve (AUC) between 0.83 and 0.96. Conclusions: The majority of differential DNA methylation is shared between SLE and pSS, however, important quantitative differences exist. Our data highlight neutrophil dysregulation as a shared mechanism, emphasizing the role of neutrophils in the pathogenesis of systemic autoimmune diseases. The current study provides evidence for genes and molecular pathways driving common and disease-specific pathogenic mechanisms., Funding Agencies|Knut and Alice Wallenberg Foundation [KAW 2011.0073]; Swedish Research Council for Medicine and Health [VR-MH Dnr 521-2014-2263, Dnr 2018-02399, Dnr 2016-01982]; Gustaf V and Queen Victorias Freemasons Foundation; County Council of Ostergotland; Swedish Rheumatism Association; King Gustaf Vs 80-year Foundation; Swedish Society of Medicine; Science for Life Laboratory, Uppsala University; Swedish Research Council (VR-RFI); Ingegerd Johansson donation; Knut and Alice Wallenberg Foundation

Published
2019
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8. Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus

Author

Carlsson Almlöf, Jonas Carlsson, Nystedt, Sara, Leonard, Dag, Eloranta, Maija-Leena, Grosso, Giorgia, Sjöwall, Christopher, Bengtsson, Anders A., Jonsen, Andreas, Gunnarsson, Iva, Svenungsson, Elisabet, Rönnblom, Lars, Sandling, Johanna K., Syvanen, Ann-Christine, Carlsson Almlöf, Jonas Carlsson, Nystedt, Sara, Leonard, Dag, Eloranta, Maija-Leena, Grosso, Giorgia, Sjöwall, Christopher, Bengtsson, Anders A., Jonsen, Andreas, Gunnarsson, Iva, Svenungsson, Elisabet, Rönnblom, Lars, Sandling, Johanna K., and Syvanen, Ann-Christine

Abstract

Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare (0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported., Funding Agencies|Knut and Alice Wallenberg Foundation; Swedish Research Council for Medicine and Health [D0283001, 2017-02000]; Swedish Rheumatism Association; King Gustaf Vs 80-year Foundation; Swedish Society of Medicine; Swedish Research Council for Infrastructures (VR-RFI)

Published
2019
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9. DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus

Author

Imgenberg-Kreuz, Juliana, Almlöf, Jonas Carlsson, Leonard, Dag, Alexsson, Andrei, Nordmark, Gunnel, Eloranta, Maija-Leena, Rantapää-Dahlqvist, Solbritt, Bengtsson, Anders A, Jönsen, Andreas, Padyukov, Leonid, Gunnarsson, Iva, Svenungsson, Elisabet, Sjöwall, Christopher, Rönnblom, Lars, Syvänen, Ann-Christine, and Sandling, Johanna K.

Subjects
Reumatologi och inflammation, gene polymorphism, systemic lupus erythematosus, immune system diseases, skin and connective tissue diseases, Rheumatology and Autoimmunity
Abstract

Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals. Methods: DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses. Results: We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus. Conclusions: Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

Published
2018

11. Treatment-Associated DNA Methylation Patterns in Systemic Lupus Erythematosus

Author

Imgenberg-Kreuz, Juliana, Almlöf, Jonas Carlsson, Leonard, Dag, Nordmark, Gunnel, Eloranta, Maija-Leena, Padyukov, Leonid, Gunnarsson, Iva, Svenungsson, Elisabet, Sjowall, Christopher, Rönnblom, Lars, Syvänen, Ann-Christine, Sandling, Johanna K., Imgenberg-Kreuz, Juliana, Almlöf, Jonas Carlsson, Leonard, Dag, Nordmark, Gunnel, Eloranta, Maija-Leena, Padyukov, Leonid, Gunnarsson, Iva, Svenungsson, Elisabet, Sjowall, Christopher, Rönnblom, Lars, Syvänen, Ann-Christine, and Sandling, Johanna K.

Published
2017

12. Novel risk genes for systemic lupus erythematosus predicted by random forest classification

Author

Almlöf, Jonas Carlsson, Alexsson, Andrei, Imgenberg-Kreuz, Juliana, Sylwan, Lina, Backlin, Christofer, Leonard, Dag, Nordmark, Gunnel, Tandre, Karolina, Eloranta, Maija-Leena, Padyukov, Leonid, Bengtsson, Christine, Jonsen, Andreas, Dahlqvist, Solbritt Rantapaa, Sjowall, Christopher, Bengtsson, Anders A., Gunnarsson, Iva, Svenungsson, Elisabet, Ronnblom, Lars, Sandling, Johanna K., Syvanen, Ann-Christine, Almlöf, Jonas Carlsson, Alexsson, Andrei, Imgenberg-Kreuz, Juliana, Sylwan, Lina, Backlin, Christofer, Leonard, Dag, Nordmark, Gunnel, Tandre, Karolina, Eloranta, Maija-Leena, Padyukov, Leonid, Bengtsson, Christine, Jonsen, Andreas, Dahlqvist, Solbritt Rantapaa, Sjowall, Christopher, Bengtsson, Anders A., Gunnarsson, Iva, Svenungsson, Elisabet, Ronnblom, Lars, Sandling, Johanna K., and Syvanen, Ann-Christine

Abstract

Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individual's SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity. Random forest classification also allowed prediction of patients at risk for lupus nephritis with an area under the curve of 0.94. By allele-specific gene expression analysis we detected cis-regulatory SNPs that affect the expression levels of six of the top 40 genes designed by the random forest analysis, indicating a regulatory role for the identified risk variants. The 40 top genes from the prediction were overrepresented for differential expression in B and T cells according to RNA-sequencing of samples from five healthy donors, with more frequent over-expression in B cells compared to T cells.

Published
2017
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13. Transancestral mapping and genetic load in systemic lupus erythematosus

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Vyse, Timothy J., Langefeld, Carl D., Ainsworth, Hannah C., Graham, Deborah S. Cunninghame, Kelly, Jennifer A., Comeau, Mary E., Marion, Miranda C., Howard, Timothy D., Ramos, Paula S., Croker, Jennifer A., Morris, David L., Sandling, Johanna K., Almlöf, Jonas Carlsson, Acevedo-Vásquez, Eduardo M., Alarcón, Graciela S., Babini, Alejandra M., Baca, Vicente, Bengtsson, Anders A., Berbotto, Guillermo A., Bijl, Marc, Brown, Elizabeth E., Brunner, Hermine I., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M., Dahlqvist, Solbritt Rantapää, D’Alfonso, Sandra, Da Silva, Berta Martins, de la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emőke, Esquivel-Valerio, Jorge A., Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., de la Torre, Ignacio García, Gilkeson, Gary S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, Diane L., Karp, David R., Kaufman, Kenneth M., Kottyan, Leah C., Kovács, László, Laustrup, Helle, Lauwerys, Bernard, Li, Quan-Zhen, Maradiaga-Ceceña, Marco A., Martín, Javier, McCune, Joseph M., McWilliams, David R., Merrill, Joan T., Miranda, Pedro, Moctezuma, José F., Nath, Swapan K., Niewold, Timothy B., Orozco, Lorena, Ortego-Centeno, Norberto, Petri, Michelle, Pineau, Christian A., Pons-Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D., Russell, Laurie P., Sabio, José M., Aguilar-Salinas, Carlos A., Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusié-Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvänen, Ann-Christine, Rönnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Vyse, Timothy J., Langefeld, Carl D., Ainsworth, Hannah C., Graham, Deborah S. Cunninghame, Kelly, Jennifer A., Comeau, Mary E., Marion, Miranda C., Howard, Timothy D., Ramos, Paula S., Croker, Jennifer A., Morris, David L., Sandling, Johanna K., Almlöf, Jonas Carlsson, Acevedo-Vásquez, Eduardo M., Alarcón, Graciela S., Babini, Alejandra M., Baca, Vicente, Bengtsson, Anders A., Berbotto, Guillermo A., Bijl, Marc, Brown, Elizabeth E., Brunner, Hermine I., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M., Dahlqvist, Solbritt Rantapää, D’Alfonso, Sandra, Da Silva, Berta Martins, de la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emőke, Esquivel-Valerio, Jorge A., Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., de la Torre, Ignacio García, Gilkeson, Gary S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, Diane L., Karp, David R., Kaufman, Kenneth M., Kottyan, Leah C., Kovács, László, Laustrup, Helle, Lauwerys, Bernard, Li, Quan-Zhen, Maradiaga-Ceceña, Marco A., Martín, Javier, McCune, Joseph M., McWilliams, David R., Merrill, Joan T., Miranda, Pedro, Moctezuma, José F., Nath, Swapan K., Niewold, Timothy B., Orozco, Lorena, Ortego-Centeno, Norberto, Petri, Michelle, Pineau, Christian A., Pons-Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D., Russell, Laurie P., Sabio, José M., Aguilar-Salinas, Carlos A., Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusié-Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvänen, Ann-Christine, Rönnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., and Silverman, Earl D.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

Published
2017

14. Transancestral mapping and genetic load in systemic lupus erythematosus

Author

Langefeld, Carl D., Ainsworth, Hannah C., Cunninghame Graham, Deborah S., Kelly, Jennifer A., Comeau, Mary E., Marion, Miranda C., Howard, Timothy D., Ramos, Paula S., Croker, Jennifer A., Morris, David L., Sandling, Johanna K., Almlöf, Jonas Carlsson, Acevedo Vásquez, Eduardo M., Alarcón, Graciela S., Babini, Alejandra M., Baca, Vicente, Bengtsson, Anders A., Berbotto, Guillermo A., Bijl, Marc, Brown, Elizabeth E., Brunner, Hermine I., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho Venegas, Jorge M., Dahlqvist, Solbritt Rantapää, D’Alfonso, Sandra, Da Silva, Berta Martins, De la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emőke, Esquivel Valerio, Jorge Antonio, Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., García de la Torre, Ignacio, Gilkeson, Gary S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, Diane L., Karp, David R., Kaufman, Kenneth M., Kottyan, Leah C., Kovács, László, Laustrup, Helle, Lauwerys, Bernard R., Li, Quan Zhen, Maradiaga Ceceña, Marco A., Martín, Javier, McCune, Joseph M., McWilliams, David R., Merrill, Joan T., Miranda, Pedro, Moctezuma, José F., Nath, Swapan K., Niewold, Timothy B., Orozco, Lorena, Ortego Centeno, Norberto, Petri, Michelle, Pineau, Christian A., Pons Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Ramsey Goldman, Rosalind, Reveille, John D., Russell, Laurie P., Sabio, José M., Aguilar Salinas, Carlos Alberto, Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusié Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvänen, Ann Christine, Rönnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., Alarcón Riquelme, Marta E., Kimberly, Robert P., Harley, John B., Wakeland, Edward K., Graham, Robert R., Gaffney, Patrick M., Vyse, Timothy J., Langefeld, Carl D., Ainsworth, Hannah C., Cunninghame Graham, Deborah S., Kelly, Jennifer A., Comeau, Mary E., Marion, Miranda C., Howard, Timothy D., Ramos, Paula S., Croker, Jennifer A., Morris, David L., Sandling, Johanna K., Almlöf, Jonas Carlsson, Acevedo Vásquez, Eduardo M., Alarcón, Graciela S., Babini, Alejandra M., Baca, Vicente, Bengtsson, Anders A., Berbotto, Guillermo A., Bijl, Marc, Brown, Elizabeth E., Brunner, Hermine I., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho Venegas, Jorge M., Dahlqvist, Solbritt Rantapää, D’Alfonso, Sandra, Da Silva, Berta Martins, De la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emőke, Esquivel Valerio, Jorge Antonio, Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., García de la Torre, Ignacio, Gilkeson, Gary S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, Diane L., Karp, David R., Kaufman, Kenneth M., Kottyan, Leah C., Kovács, László, Laustrup, Helle, Lauwerys, Bernard R., Li, Quan Zhen, Maradiaga Ceceña, Marco A., Martín, Javier, McCune, Joseph M., McWilliams, David R., Merrill, Joan T., Miranda, Pedro, Moctezuma, José F., Nath, Swapan K., Niewold, Timothy B., Orozco, Lorena, Ortego Centeno, Norberto, Petri, Michelle, Pineau, Christian A., Pons Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Ramsey Goldman, Rosalind, Reveille, John D., Russell, Laurie P., Sabio, José M., Aguilar Salinas, Carlos Alberto, Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusié Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvänen, Ann Christine, Rönnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., Alarcón Riquelme, Marta E., Kimberly, Robert P., Harley, John B., Wakeland, Edward K., Graham, Robert R., Gaffney, Patrick M., and Vyse, Timothy J.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (B50% of these regions have multiple independent associations); these include 24 novel SLE regions (Po5 10 8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE

Published
2017

15. Variants in BANK1are associated with lupus nephritis of European ancestry

Author

Bolin, Karin, Imgenberg-Kreuz, Juliana, Leonard, Dag, Sandling, Johanna K., Alexsson, Andrei, Pucholt, Pascal, Haarhaus, Malena Loberg, Almlöf, Jonas Carlsson, Nititham, Joanne, Jönsen, Andreas, Sjöwall, Christopher, Bengtsson, Anders A., Rantapää-Dahlqvist, Solbritt, Svenungsson, Elisabet, Gunnarsson, Iva, Syvänen, Ann-Christine, Lerang, Karoline, Troldborg, Anne, Voss, Anne, Molberg, Øyvind, Jacobsen, Søren, Criswell, Lindsey, Rönnblom, Lars, and Nordmark, Gunnel

Abstract

The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n= 1091) and replication cohort 1 (US, n= 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n= 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p< 1 × 10−4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y,and ACER3) in the discovery cohort. Variants in BANK1showed the strongest association with LN in replication cohort 1 (p= 9.5 × 10−4) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1and LN in replication cohort 2 (p= 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p= 2.2 × 10−7). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1variants. To conclude, we describe genetic variations in BANK1associated with LN and evidence for genetic regulation of DNA methylation within the BANK1locus. This indicates a role for BANK1in LN pathogenesis.

Published
2021
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16. Novel risk genes for systemic lupus erythematosus predicted by random forest classification

Author

Almlöf, Jonas Carlsson, primary, Alexsson, Andrei, additional, Imgenberg-Kreuz, Juliana, additional, Sylwan, Lina, additional, Bäcklin, Christofer, additional, Leonard, Dag, additional, Nordmark, Gunnel, additional, Tandre, Karolina, additional, Eloranta, Maija-Leena, additional, Padyukov, Leonid, additional, Bengtsson, Christine, additional, Jönsen, Andreas, additional, Dahlqvist, Solbritt Rantapää, additional, Sjöwall, Christopher, additional, Bengtsson, Anders A., additional, Gunnarsson, Iva, additional, Svenungsson, Elisabet, additional, Rönnblom, Lars, additional, Sandling, Johanna K., additional, and Syvänen, Ann-Christine, additional

Published
2017
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17. Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes

Author

Imgenberg-Kreuz, Juliana, Sandling, Johanna K., Almlöf, Jonas Carlsson, Nordlund, Jessica, Signér, Linnea, Norheim, Katrine Braekke, Omdal, Roald, Rönnblom, Lars, Eloranta, Maija-Leena, Syvänen, Ann-Christine, Nordmark, Gunnel, Imgenberg-Kreuz, Juliana, Sandling, Johanna K., Almlöf, Jonas Carlsson, Nordlund, Jessica, Signér, Linnea, Norheim, Katrine Braekke, Omdal, Roald, Rönnblom, Lars, Eloranta, Maija-Leena, Syvänen, Ann-Christine, and Nordmark, Gunnel

Abstract

OBJECTIVES: Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls. METHODS: Genome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed. RESULTS: We identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed. CONCLUSIONS: Our study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology., De 2 första författarna delar förstaförfattarskapet.

Published
2016
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18. CopyNumber450kCancer : baseline correction for accurate copy number calling from the 450k methylation array

Author

Marzouka, Nour-al-dain, Nordlund, Jessica, Bäcklin, Christofer L., Lönnerholm, Gudmar, Syvänen, Ann-Christine, Almlöf, Jonas Carlsson, Marzouka, Nour-al-dain, Nordlund, Jessica, Bäcklin, Christofer L., Lönnerholm, Gudmar, Syvänen, Ann-Christine, and Almlöf, Jonas Carlsson

Abstract

The Illumina Infinium HumanMethylation450 BeadChip (450k) is widely used for the evaluation of DNA methylation levels in large-scale datasets, particularly in cancer. The 450k design allows copy number variant (CNV) calling using existing bioinformatics tools. However, in cancer samples, numerous large-scale aberrations cause shifting in the probe intensities and thereby may result in erroneous CNV calling. Therefore, a baseline correction process is needed. We suggest the maximum peak of probe segment density to correct the shift in the intensities in cancer samples.

Published
2016
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19. Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes

Author

Lindqvist, C. Mårten, Lundmark, Anders, Nordlund, Jessica, Freyhult, Eva, Ekman, Diana, Almlöf, Jonas Carlsson, Raine, Amanda, Övernäs, Elin, Abrahamsson, Jonas, Frost, Britt-Marie, Grander, Dan, Heyman, Mats, Palle, Josefine, Forestier, Erik, Lönnerholm, Gudmar, Berglund, Eva C., Syvänen, Ann-Christine, Lindqvist, C. Mårten, Lundmark, Anders, Nordlund, Jessica, Freyhult, Eva, Ekman, Diana, Almlöf, Jonas Carlsson, Raine, Amanda, Övernäs, Elin, Abrahamsson, Jonas, Frost, Britt-Marie, Grander, Dan, Heyman, Mats, Palle, Josefine, Forestier, Erik, Lönnerholm, Gudmar, Berglund, Eva C., and Syvänen, Ann-Christine

Abstract

To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency.

Published
2016
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20. Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes

Author

Lindqvist, C. Mårten, primary, Lundmark, Anders, additional, Nordlund, Jessica, additional, Freyhult, Eva, additional, Ekman, Diana, additional, Almlöf, Jonas Carlsson, additional, Raine, Amanda, additional, Övernäs, Elin, additional, Abrahamsson, Jonas, additional, Frost, Britt-Marie, additional, Grandér, Dan, additional, Heyman, Mats, additional, Palle, Josefine, additional, Forestier, Erik, additional, Lönnerholm, Gudmar, additional, Berglund, Eva C., additional, and Syvänen, Ann-Christine, additional

Published
2016
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21. Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes

Author

Imgenberg-Kreuz, Juliana, primary, Sandling, Johanna K, additional, Almlöf, Jonas Carlsson, additional, Nordlund, Jessica, additional, Signér, Linnea, additional, Norheim, Katrine Braekke, additional, Omdal, Roald, additional, Rönnblom, Lars, additional, Eloranta, Maija-Leena, additional, Syvänen, Ann-Christine, additional, and Nordmark, Gunnel, additional

Published
2016
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22. Hypomethylation in Enhancer and Promoter Regions of Interferon Regulated Genes in Multiple Tissues Is Associated with Primary Sjogren's Syndrome

Author

Imgenberg-Kreuz, Juliana, Sandling, Johanna K., Almlöf, Jonas Carlsson, Nordlund, Jessica, Signer, Linnea, Norheim, Katrine B., Omdal, Roald, Eloranta, Majia-Leena, Rönnblom, Lars, Syvanen, Ann-Christine, Nordmark, Gunnel, Imgenberg-Kreuz, Juliana, Sandling, Johanna K., Almlöf, Jonas Carlsson, Nordlund, Jessica, Signer, Linnea, Norheim, Katrine B., Omdal, Roald, Eloranta, Majia-Leena, Rönnblom, Lars, Syvanen, Ann-Christine, and Nordmark, Gunnel

Published
2015
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23. Genome-Wide DNA Methylation Analysis of CD19+B Cells in Primary Sjogren's Syndrome

Author

Nordmark, Gunnel, Imgenberg-Kreuz, Juliana, Almlöf, Jonas Carlsson, Nordlund, Jessica, Omdal, Roald, Norheim, Katrine B., Eloranta, Maija-Leena, Rönnblom, Lars, Sandling, Johanna K., Nordmark, Gunnel, Imgenberg-Kreuz, Juliana, Almlöf, Jonas Carlsson, Nordlund, Jessica, Omdal, Roald, Norheim, Katrine B., Eloranta, Maija-Leena, Rönnblom, Lars, and Sandling, Johanna K.

Published
2014

24. Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression

Author

Almlöf, Jonas Carlsson, Lundmark, Per, Lundmark, Anders, Ge, B., Maouche, S., Göring, H. H. H., Liljedahl, Ulrika, Enström, Camilla, Brocheton, J., Proust, C., Godefroy, T., Sambrook, J. G., Jolley, J., Crisp-Hihn, A., Foad, N., Lloyd-Jones, H., Stephens, J., Gwilliam, R., Rice, C. M., Hengstenberg, C., Samani, N. J., Erdmann, J., Schunkert, H., Pastinen, T., Deloukas, P., Goodall, A. H., Ouwehand, W. H., Cambien, F., Syvänen, Ann-Christine, Almlöf, Jonas Carlsson, Lundmark, Per, Lundmark, Anders, Ge, B., Maouche, S., Göring, H. H. H., Liljedahl, Ulrika, Enström, Camilla, Brocheton, J., Proust, C., Godefroy, T., Sambrook, J. G., Jolley, J., Crisp-Hihn, A., Foad, N., Lloyd-Jones, H., Stephens, J., Gwilliam, R., Rice, C. M., Hengstenberg, C., Samani, N. J., Erdmann, J., Schunkert, H., Pastinen, T., Deloukas, P., Goodall, A. H., Ouwehand, W. H., Cambien, F., and Syvänen, Ann-Christine

Abstract

A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.

Published
2012
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25. Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression

Author

Almlöf, Jonas Carlsson, primary, Lundmark, Per, additional, Lundmark, Anders, additional, Ge, Bing, additional, Maouche, Seraya, additional, Göring, Harald H. H., additional, Liljedahl, Ulrika, additional, Enström, Camilla, additional, Brocheton, Jessy, additional, Proust, Carole, additional, Godefroy, Tiphaine, additional, Sambrook, Jennifer G., additional, Jolley, Jennifer, additional, Crisp-Hihn, Abigail, additional, Foad, Nicola, additional, Lloyd-Jones, Heather, additional, Stephens, Jonathan, additional, Gwilliam, Rhian, additional, Rice, Catherine M., additional, Hengstenberg, Christian, additional, Samani, Nilesh J., additional, Erdmann, Jeanette, additional, Schunkert, Heribert, additional, Pastinen, Tomi, additional, Deloukas, Panos, additional, Goodall, Alison H., additional, Ouwehand, Willem H., additional, Cambien, François, additional, and Syvänen, Ann-Christine, additional

Published
2012
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26. Variants in BANK1 are associated with lupus nephritis

Author

Bolin, Karin, Leonard, Dag, Sandling, Johanna K., Imgenberg-Kreuz, Juliana, Alexsson, Andrei, Pucholt, Pascal, Loberg Haarhaus, Malena, Almlöf, Jonas Carlsson, Nititham, Joanne, Jönsen, Andreas, Sjöwall, Christopher, Bengtsson, Anders A, Rantapää-Dahlqvist, Solbritt, Svenungsson, Elisabet, Gunnarsson, Iva, Syvänen, Ann-Christine, Lerang, Karoline, Troldborg, Anne, Voss, Anne, Molberg, Øyvind, Jacobsen, Søren, Criswell, Lindsey, Rönnblom, Lars, Nordmark, Gunnel, Bolin, Karin, Leonard, Dag, Sandling, Johanna K., Imgenberg-Kreuz, Juliana, Alexsson, Andrei, Pucholt, Pascal, Loberg Haarhaus, Malena, Almlöf, Jonas Carlsson, Nititham, Joanne, Jönsen, Andreas, Sjöwall, Christopher, Bengtsson, Anders A, Rantapää-Dahlqvist, Solbritt, Svenungsson, Elisabet, Gunnarsson, Iva, Syvänen, Ann-Christine, Lerang, Karoline, Troldborg, Anne, Voss, Anne, Molberg, Øyvind, Jacobsen, Søren, Criswell, Lindsey, Rönnblom, Lars, and Nordmark, Gunnel

Abstract

Background: Lupus nephritis (LN) is a cause of significant morbidity in SLE. While the genetic background to SLE has been well characterized, less is known about genes predisposing to LN. Methods: The study consisted of 2886 SLE patients, including 947 (33%) with LN. The discovery cohort (Sweden, n=1091) and replication cohort 1 (US, n=962) were genotyped on the Immunochip and replication cohort 2 (Norway/Denmark, n=833) on a custom array chip. Allele frequencies were compared between patients with LN, proliferative nephritis, end-stage renal disease and LN negative patients. SNPs with p-value <0.001 in the discovery cohort were analyzed in replication cohort 1. Ten SNPs associated with LN in the discovery cohort (p<0.0002) were genotyped in replication cohort 2. DNA methylation data were available for 180 LN patients from the discovery cohort. Results: In the discovery cohort, six gene loci were associated with LN (p<1x10-4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y and PHCA). SNPs in BANK1 showed the strongest association with LN in replication cohort 1 (p=9.5x10-4), with a tendency for an association in replication cohort 2 (p=0.052). In a meta-analysis of all three cohorts the association between LN and BANK1 rs4699259, was strengthened (p=1.7x10‑7). There were no associations to proliferative nephritis or ESRD in the meta-analysis. Methylation quantitative trait loci (MeQTL) effects between a CpG site and several SNPs in BANK1 were identified. Conclusion: Genetic variations in BANK1 are associated with LN. There is evidence for genetic regulation of DNA methylation within the BANK1 locus, however, the exact role of BANK1 in LN pathogenesis remains to be elucidated.

27. DNA methylation classification in combination with RNA-sequencing for subtype discovery in pediatric B-cell precursor acute lymphoblastic leukemia

Author

Marincevic-Zuniga, Yanara, Nystedt, Sara, Nilsson, Sara, Almlöf, Jonas Carlsson, Lilljebjörn, Henrik, Fioretos, Thoas, Flaegstad, Trond, Forestier, Erik, Heyman, Mats, Kanerva, Jukka, Schmiegelow, Kjeld, Lönnerholm, Gudmar, Nordlund, Jessica, Marincevic-Zuniga, Yanara, Nystedt, Sara, Nilsson, Sara, Almlöf, Jonas Carlsson, Lilljebjörn, Henrik, Fioretos, Thoas, Flaegstad, Trond, Forestier, Erik, Heyman, Mats, Kanerva, Jukka, Schmiegelow, Kjeld, Lönnerholm, Gudmar, and Nordlund, Jessica

28. Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes.

Author

Almlöf JC, Lundmark P, Lundmark A, Ge B, Pastinen T, Goodall AH, Cambien F, Deloukas P, Ouwehand WH, and Syvänen AC

Subjects
Cells, Cultured, Gene Expression, Gene Expression Regulation, Genome-Wide Association Study, Humans, Molecular Sequence Annotation, Open Reading Frames, RNA, Long Noncoding metabolism, Monocytes metabolism, Polymorphism, Single Nucleotide, RNA, Long Noncoding genetics
Abstract

We applied genome-wide allele-specific expression analysis of monocytes from 188 samples. Monocytes were purified from white blood cells of healthy blood donors to detect cis-acting genetic variation that regulates the expression of long non-coding RNAs. We analysed 8929 regions harboring genes for potential long non-coding RNA that were retrieved from data from the ENCODE project. Of these regions, 60% were annotated as intergenic, which implies that they do not overlap with protein-coding genes. Focusing on the intergenic regions, and using stringent analysis of the allele-specific expression data, we detected robust cis-regulatory SNPs in 258 out of 489 informative intergenic regions included in the analysis. The cis-regulatory SNPs that were significantly associated with allele-specific expression of long non-coding RNAs were enriched to enhancer regions marked for active or bivalent, poised chromatin by histone modifications. Out of the lncRNA regions regulated by cis-acting regulatory SNPs, 20% (n = 52) were co-regulated with the closest protein coding gene. We compared the identified cis-regulatory SNPs with those in the catalog of SNPs identified by genome-wide association studies of human diseases and traits. This comparison identified 32 SNPs in loci from genome-wide association studies that displayed a strong association signal with allele-specific expression of non-coding RNAs in monocytes, with p-values ranging from 6.7×10(-7) to 9.5×10(-89). The identified cis-regulatory SNPs are associated with diseases of the immune system, like multiple sclerosis and rheumatoid arthritis.

Published
2014
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