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Syvänen, Ann-Christine
Alternative names
Publications (10 of 263) Show all publications
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, 2019-2032 p.Article 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, 485-487 p.Article 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
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, 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: 2017-11-29Bibliographically 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, 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
Raine, A., Manlig, E., Wahlberg, P., Syvänen, A.-C. & Nordlund, J. (2017). SPlinted Ligation Adapter Tagging (SPLAT), a novel library preparation method for whole genome bisulphite sequencing. Nucleic Acids Research, 45(6), Article ID e36.
Open this publication in new window or tab >>SPlinted Ligation Adapter Tagging (SPLAT), a novel library preparation method for whole genome bisulphite sequencing
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2017 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 6, e36Article in journal (Refereed) Published
Abstract [en]

Sodium bisulphite treatment of DNA combined with next generation sequencing (NGS) is a powerful combination for the interrogation of genome-wide DNA methylation profiles. Library preparation for whole genome bisulphite sequencing (WGBS) is challenging due to side effects of the bisulphite treatment, which leads to extensive DNA damage. Recently, a new generation of methods for bisulphite sequencing library preparation have been devised. They are based on initial bisulphite treatment of the DNA, followed by adaptor tagging of single stranded DNA fragments, and enable WGBS using low quantities of input DNA. In this study, we present a novel approach for quick and cost effectiveWGBS library preparation that is based on splinted adaptor tagging (SPLAT) of bisulphite-converted single-stranded DNA. Moreover, we validate SPLAT against three commercially available WGBS library preparation techniques, two of which are based on bisulphite treatment prior to adaptor tagging and one is a conventional WGBS method.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-320632 (URN)10.1093/nar/gkw1110 (DOI)000398376200001 ()27899585 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RBc08-008
Available from: 2017-08-14 Created: 2017-08-14 Last updated: 2017-08-14Bibliographically approved
Ameur, A., Dahlberg, J., Olason, P., Vezzi, F., Karlsson, R., Martin, M., . . . Gyllensten, U. B. (2017). SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population. European Journal of Human Genetics, 25(11), 1253-1260.
Open this publication in new window or tab >>SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population
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2017 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 25, no 11, 1253-1260 p.Article in journal (Refereed) Published
Abstract [en]

Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-337314 (URN)10.1038/ejhg.2017.130 (DOI)000412823800012 ()28832569 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg Foundation, 2014.0272Swedish Research CouncilSwedish National Infrastructure for Computing (SNIC), sens2016003EU, European Research Council, 282330
Available from: 2018-01-08 Created: 2018-01-08 Last updated: 2018-01-08Bibliographically approved
Langefeld, C. D., Ainsworth, H. C., Graham, D. S. C., Kelly, J. A., Comeau, M. E., Marion, M. C., . . . Vyse, T. J. (2017). Transancestral mapping and genetic load in systemic lupus erythematosus. Nature Communications, 8, Article ID 16021.
Open this publication in new window or tab >>Transancestral mapping and genetic load in systemic lupus erythematosus
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, 16021Article in journal (Refereed) Published
Abstract [en]

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 (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-331233 (URN)10.1038/ncomms16021 (DOI)000405680100001 ()28714469 (PubMedID)
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-11-29Bibliographically approved
Marincevic-Zuniga, Y., Dahlberg, J., Nilsson, S., Raine, A., Nystedt, S., Lindqvist, C. M., . . . Syvänen, A.-C. (2017). Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles. Journal of Hematology & Oncology, 10, Article ID 148.
Open this publication in new window or tab >>Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles
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2017 (English)In: Journal of Hematology & Oncology, ISSN 1756-8722, E-ISSN 1756-8722, Vol. 10, 148Article in journal (Refereed) Published
Abstract [en]

Background: Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). In this study, we performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts. Methods: We combined fusion gene detection with genome-wide DNA methylation analysis, gene expression profiling, and targeted sequencing to determine molecular signatures of emerging ALL subtypes. Results: We identified 64 unique fusion events distributed among 80 individual patients, of which over 50% have not previously been reported in ALL. Although the majority of the fusion genes were found only in a single patient, we identified several recurrent fusion gene families defined by promiscuous fusion gene partners, such as ETV6, RUNX1, PAX5, and ZNF384, or recurrent fusion genes, such as DUX4-IGH. Our data show that patients harboring these fusion genes displayed characteristic genome-wide DNA methylation and gene expression signatures in addition to distinct patterns in single nucleotide variants and recurrent copy number alterations. Conclusion: Our study delineates the fusion gene landscape in pediatric ALL, including both known and novel fusion genes, and highlights fusion gene families with shared molecular etiologies, which may provide additional information for prognosis and therapeutic options in the future.

Keyword
Pediatric acute lymphoblastic leukemia, RNA sequencing, Fusion genes, BCP-ALL, T-ALL, Translocation
National Category
Cancer and Oncology Pediatrics
Identifiers
urn:nbn:se:uu:diva-332658 (URN)10.1186/s13045-017-0515-y (DOI)000408001300001 ()28806978 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RBc08-008Swedish Cancer Society, 130440, 160711Swedish Childhood Cancer Foundation, 11098Swedish Research Council, C0524801, 2016-03691_3
Note

De 2 sista författarna delar sistaförfattarskapet.

Available from: 2017-10-31 Created: 2017-10-31 Last updated: 2017-11-29Bibliographically approved
Madrigal, I., Alvarez-Mora, M. I., Rosell, J., Rodríguez-Revenga, L., Karlberg, O., Sauer, S., . . . Mila, M. (2016). A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability.. European Journal of Human Genetics, 24(8), 1117-1123.
Open this publication in new window or tab >>A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability.
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2016 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 24, no 8, 1117-1123 p.Article in journal (Refereed) Published
Abstract [en]

The IQSEC2 gene is located on chromosome Xp11.22 and encodes a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases. This gene is known to have a significant role in cytoskeletal organization, dendritic spine morphology and synaptic organization. Variants in IQSEC2 cause moderate to severe intellectual disability in males and a variable phenotype in females because this gene escapes from X-chromosome inactivation. Here we report on the first splicing variant in IQSEC2 (g.88032_88033del; NG_021296.1) that co-segregates in a family diagnosed with an X-linked form of ID. In a percentage of the cells, the variant activates an intraexonic splice acceptor site that abolishes 26 amino acids from the highly conserved PH domain of IQSEC2 and creates a premature stop codon 36 amino acids later in exon 13. Interestingly, the percentage of aberrant splicing seems to correlate with the severity of the disease in each patient. The impact of this variant in the target tissue is unknown, but we can hypothesize that these differences may be related to the amount of abnormal IQSEC2 transcript. To our knowledge, we are reporting a novel mechanism of IQSEC2 involvement in ID. Variants that affect splicing are related to many genetic diseases and the understanding of their role in disease expands potential opportunities for gene therapy. Modulation of aberrant splicing transcripts can become a potent therapeutic approach for many of these diseases.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-300957 (URN)10.1038/ejhg.2015.267 (DOI)000380390300008 ()26733290 (PubMedID)
External cooperation:
Funder
EU, FP7, Seventh Framework Programme, 262055
Available from: 2016-08-16 Created: 2016-08-16 Last updated: 2017-11-28Bibliographically approved
Marzouka, N.-a., Nordlund, J., Bäcklin, C. L., Lönnerholm, G., Syvänen, A.-C. & Almlöf, J. C. (2016). CopyNumber450kCancer: baseline correction for accurate copy number calling from the 450k methylation array. Bioinformatics, 32(7), 1080-1082.
Open this publication in new window or tab >>CopyNumber450kCancer: baseline correction for accurate copy number calling from the 450k methylation array
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2016 (English)In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, no 7, 1080-1082 p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-296859 (URN)10.1093/bioinformatics/btv652 (DOI)000374236400016 ()26553913 (PubMedID)
Funder
Swedish Cancer Society, CAN2010/592Swedish Research Council, 90559401Swedish Foundation for Strategic Research , RBc08-008
Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2017-11-28Bibliographically approved
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