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Syvänen, Ann-Christine
Alternative names
Publications (10 of 273) Show all publications
Pullabhatla, V., Roberts, A. L., Lewis, M. J., Mauro, D., Morris, D. L., Odhams, C. A., . . . Vyse, T. J. (2018). De novo mutations implicate novel genes in systemic lupus erythematosus. Human Molecular Genetics, 27(3), 421-429
Open this publication in new window or tab >>De novo mutations implicate novel genes in systemic lupus erythematosus
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2018 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 3, p. 421-429Article in journal (Refereed) Published
Abstract [en]

The omnigenic model of complex disease stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing, high-density imputation, and in vitro cellular assays, we identify candidate core genes in the pathogenesis of systemic lupus erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies. In a follow-up cohort of 10, 995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. Gene-level analyses indicate three functional candidates: DNMT3A, PRKCD, and C1QTNF4. We identify a burden of rare variants across PRKCD associated with SLE risk (P = 0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P = 0.0005 and P = 0.0033). We further characterise the TNF-dependent functions of the third candidate gene C1QTNF4 on NF-kappa B activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results identify three novel genes in SLE susceptibility and support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.

Place, publisher, year, edition, pages
Oxford University Press, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-346884 (URN)10.1093/hmg/ddx407 (DOI)000424136000002 ()29177435 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2011.0073
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-03-27Bibliographically approved
Imgenberg-Kreuz, J., Almlöf, J. C., Leonard, D., Alexsson, A., Nordmark, G., Eloranta, M.-L., . . . Sandling, J. K. (2018). DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus. Annals of the Rheumatic Diseases, 77(5), 736-743
Open this publication in new window or tab >>DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
gene polymorphism, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-342164 (URN)10.1136/annrheumdis-2017-212379 (DOI)000430492600020 ()29437559 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2011.0073Swedish Research Council, 521-2014-2263; 521-2013-2830; 521-2014-3954; 2016-01982; 350-2012-256AstraZenecaSwedish Society for Medical Research (SSMF)Swedish Rheumatism AssociationThe King Gustaf V's Jubilee FoundationSwedish Heart Lung FoundationStockholm County CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-06-19Bibliographically approved
Imgenberg-Kreuz, J., Sandling, J. K., Bjork, A., Nordlund, J., Kvarnstrom, M., Eloranta, M.-L., . . . Nordmark, G. (2018). Transcription profiling of peripheral B cells in antibody-positive primary Sjogren's syndrome reveals upregulated expression of CX3CR1 and a type I and type II interferon signature. Scandinavian Journal of Immunology, 87(5), Article ID UNSP e12662.
Open this publication in new window or tab >>Transcription profiling of peripheral B cells in antibody-positive primary Sjogren's syndrome reveals upregulated expression of CX3CR1 and a type I and type II interferon signature
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2018 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 87, no 5, article id UNSP e12662Article in journal (Refereed) Published
Abstract [en]

B cells play a key role in the pathogenesis of primary Sjogren's syndrome (pSS). The aim of this study was to analyse the transcriptome of CD19+ B cells from patients with pSS and healthy controls to decipher the B cell-specific contribution to pSS. RNA from purified CD19+ B cells from 12 anti-SSA antibody-positive untreated female patients with pSS and 20 healthy blood donors was subjected to whole transcriptome sequencing. A false discovery rate corrected significance threshold of <0.05 was applied to define differential gene expression. As validation, gene expression in B cells from 17 patients with pSS and 16 healthy controls was analysed using a targeted gene panel. RNA-sequencing identified 4047 differentially expressed autosomal genes in pSS B cells. Upregulated expression of type I and type II interferon (IFN)-induced genes was observed, establishing an IFN signature in pSS B cells. Among the top upregulated and validated genes were CX3CR1, encoding the fractalkine receptor involved in regulation of B-cell malignancies, CCL5/RANTES and CCR1. Increased expression of several members of the TNF superfamily was also identified; TNFSF4/Ox40L, TNFSF10/TRAIL, TNFSF13B/BAFF, TNFRSF17/BCMA as well as S100A8 and -A9/calprotectin, TLR7, STAT1 and STAT2. Among genes with downregulated expression in pSS B cells were SOCS1 and SOCS3, CD70 and TNFAIP3/A20. We conclude that B cells from patients with anti-SSA antibody-positive pSS display immune activation with upregulated expression of chemokines, chemokine receptors and a prominent type I and type II IFN signature, while suppressors of cytokine signalling are downregulated. This adds insight into the autoimmune process and suggests potential targets for future functional studies.

National Category
Immunology in the medical area Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-354096 (URN)10.1111/sji.12662 (DOI)000430398400006 ()29655283 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, 2011.0073Swedish Research Council, 2012-2148Swedish Research Council, 350-2012-256Swedish Research Council, 521-2013-2830Swedish Research Council, 521-2014-2263Swedish Research Council, 2016-01982Knut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-06-19Bibliographically approved
Manning, A., Highland, H. M., Gasser, J., Sim, X., Tukiainen, T., Fontanillas, P., . . . Lindgren, C. M. (2017). A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. Diabetes, 66(7), 2019-2032
Open this publication in new window or tab >>A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
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2017 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 7, p. 2019-2032Article in journal (Refereed) Published
Abstract [en]

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC, 2017
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-328990 (URN)10.2337/db16-1329 (DOI)000403778600030 ()28341696 (PubMedID)
Available from: 2017-09-08 Created: 2017-09-08 Last updated: 2017-09-08Bibliographically approved
Sarkisyan, D., Bazov, I., Watanabe, H., Kononenko, O., Syvänen, A.-C., Schumann, G., . . . Bakalkin, G. (2017). Damaged reward areas in human alcoholics: neuronal proportion decline and astrocyte activation [Letter to the editor]. Acta Neuropathologica, 133(3), 485-487
Open this publication in new window or tab >>Damaged reward areas in human alcoholics: neuronal proportion decline and astrocyte activation
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2017 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 133, no 3, p. 485-487Article in journal, Letter (Refereed) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-316837 (URN)10.1007/s00401-017-1675-0 (DOI)000394961100011 ()28097436 (PubMedID)
Note

Shared first authorship for Sarkisyan D., Bazov I.

Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2017-04-28Bibliographically approved
Flannick, J., Fuchsberger, C., Mahajan, A., Teslovich, T. M., Agarwala, V., Gaulton, K. J., . . . McCarthy, M. I. (2017). Data Descriptor: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls. Scientific Data, 4, Article ID 170179.
Open this publication in new window or tab >>Data Descriptor: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
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2017 (English)In: Scientific Data, E-ISSN 2052-4463, Vol. 4, article id 170179Article in journal (Refereed) Published
Abstract [en]

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

National Category
Endocrinology and Diabetes Medical Genetics
Identifiers
urn:nbn:se:uu:diva-339776 (URN)10.1038/sdata.2017.179 (DOI)000418568400001 ()29257133 (PubMedID)
Funder
AstraZeneca
Note

Erratum in: Scientific Data, volume 5, Article number: 180002, 2018

Doi:10.1038/sdata.2018.2

Available from: 2018-02-09 Created: 2018-02-09 Last updated: 2018-05-08Bibliographically approved
Nolte, I. M., Munoz, M. L., Tragante, V., Amare, A. T., Jansen, R., Vaez, A., . . . de Geus, E. J. C. (2017). Genetic loci associated with heart rate variability and their effects on cardiac disease risk. Nature Communications, 8, Article ID 15805.
Open this publication in new window or tab >>Genetic loci associated with heart rate variability and their effects on cardiac disease risk
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15805Article in journal (Refereed) Published
Abstract [en]

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-329672 (URN)10.1038/ncomms15805 (DOI)000403216600001 ()28613276 (PubMedID)
Available from: 2017-09-19 Created: 2017-09-19 Last updated: 2018-02-19Bibliographically approved
Reid, S., Alexsson, A., Frodlund, M., Sandling, J. K., Svenungsson, E., Jonsen, A., . . . Leonard, D. (2017). High Genetic Risk Score Is Associated with Increased Organ Damage in SLE. Arthritis & Rheumatology, 69(S10), Article ID 1638.
Open this publication in new window or tab >>High Genetic Risk Score Is Associated with Increased Organ Damage in SLE
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2017 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 1638Article in journal, Meeting abstract (Other academic) Published
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-346798 (URN)000411824103162 ()
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-03-22Bibliographically approved
Strawbridge, R. J., Silveira, A., den Hoed, M., Gustafsson, S., Luan, J., Rybin, D., . . . Hamsten, A. (2017). Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation. Atherosclerosis, 266, 196-204
Open this publication in new window or tab >>Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation
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2017 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 266, p. 196-204Article in journal (Refereed) Published
Abstract [en]

Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.

Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.

Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.

Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.

Keywords
Proinsulin, Atherosclerosis, Intima-media-thickness, Single nucleotide polymorphisms, Genetic variants, Mendelian randomisation
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-341363 (URN)10.1016/j.atherosclerosis.2017.09.031 (DOI)000414069700027 ()29040868 (PubMedID)
Funder
Swedish Research Council, 8691 09533 2012-1397 2015-03657Swedish Heart Lung Foundation, 20120197 20140543EU, European Research CouncilKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research Stockholm County Council, 592229EU, FP7, Seventh Framework Programme, IMI/115006Swedish National Infrastructure for Computing (SNIC), b2011036
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2018-02-08Bibliographically approved
Carlsson Almlöf, J., Alexsson, A., Imgenberg-Kreuz, J., Sylwan, L., Bäcklin, C., Leonard, D., . . . Syvänen, A.-C. (2017). Novel risk genes for systemic lupus erythematosus predicted by random forest classification. Scientific Reports, 7, Article ID 6236.
Open this publication in new window or tab >>Novel risk genes for systemic lupus erythematosus predicted by random forest classification
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6236Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-333524 (URN)10.1038/s41598-017-06516-1 (DOI)000406260100040 ()28740209 (PubMedID)
Funder
Swedish Research Council, 521-2014-2263, 521-2013-2830
Available from: 2017-11-14 Created: 2017-11-14 Last updated: 2017-11-14Bibliographically approved
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