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Liljedahl, Ulrika
Publications (10 of 15) Show all publications
Raine, A., Liljedahl, U. & Nordlund, J. (2018). Data quality of whole genome bisulfite sequencing on Illumina platforms. PLoS ONE, 13(4), Article ID e0195972.
Open this publication in new window or tab >>Data quality of whole genome bisulfite sequencing on Illumina platforms
2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0195972Article in journal (Refereed) Published
Abstract [en]

The powerful HiSeq X sequencers with their patterned flowcell technology and fast turnaround times are instrumental for many large-scale genomic and epigenomic studies. However, assessment of DNA methylation by sodium bisulfite treatment results in sequencing libraries of low diversity, which may impact data quality and yield. In this report we assess the quality of WGBS data generated on the HiSeq X system in comparison with data generated on the HiSeq 2500 system and the newly released NovaSeq system. We report a systematic issue with low basecall quality scores assigned to guanines in the second read of WGBS when using certain Real Time Analysis (RTA) software versions on the HiSeq X sequencer, reminiscent of an issue that was previously reported with certain HiSeq 2500 software versions. However, with the HD.3.4.0 /RTA 2.7.7 software upgrade for the HiSeq X system, we observed an overall improved quality and yield of the WGBS data generated, which in turn empowers cost-effective and high quality DNA methylation studies.

National Category
Computer Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-354966 (URN)10.1371/journal.pone.0195972 (DOI)000430290200071 ()29668744 (PubMedID)
Note

Raw sequencing reads are available from NCBIs short read archive (SRA). Bioproject number PRJNA407440 and GEO accession number GSE89213.

Available from: 2018-06-25 Created: 2018-06-25 Last updated: 2018-06-25Bibliographically approved
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
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, p. 1253-1260Article 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: 2018-08-27Bibliographically approved
Guy, L., Jernberg, C., Norling, J. A., Ivarsson, S., Hedenstrom, I., Melefors, O., . . . Andersson, S. G. E. (2013). Adaptive Mutations and Replacements of Virulence Traits in the Escherichia coli O104:H4 Outbreak Population. PLoS ONE, 8(5), e63027
Open this publication in new window or tab >>Adaptive Mutations and Replacements of Virulence Traits in the Escherichia coli O104:H4 Outbreak Population
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e63027-Article in journal (Refereed) Published
Abstract [en]

The sequencing of highly virulent Escherichia coli O104:H4 strains isolated during the outbreak of bloody diarrhea and hemolytic uremic syndrome in Europe in 2011 revealed a genome that contained a Shiga toxin encoding prophage and a plasmid encoding enteroaggregative fimbriae. Here, we present the draft genome sequence of a strain isolated in Sweden from a patient who had travelled to Tunisia in 2010 (E112/10) and was found to differ from the outbreak strains by only 38 SNPs in non-repetitive regions, 16 of which were mapped to the branch to the outbreak strain. We identified putatively adaptive mutations in genes for transporters, outer surface proteins and enzymes involved in the metabolism of carbohydrates. A comparative analysis with other historical strains showed that E112/10 contained Shiga toxin prophage genes of the same genotype as the outbreak strain, while these genes have been replaced by a different genotype in two otherwise very closely related strains isolated in the Republic of Georgia in 2009. We also present the genome sequences of two enteroaggregative E. coli strains affiliated with phylogroup A (C43/90 and C48/93) that contain the agg genes for the AAF/I-type fimbriae characteristic of the outbreak population. Interestingly, C43/90 also contained a tet/mer antibiotic resistance island that was nearly identical in sequence to that of the outbreak strain, while the corresponding island in the Georgian strains was most similar to E. coli strains of other serotypes. We conclude that the pan-genome of the outbreak population is shared with strains of the A phylogroup and that its evolutionary history is littered with gene replacement events, including most recently independent acquisitions of antibiotic resistance genes in the outbreak strains and its nearest neighbors. The results are summarized in a refined evolutionary model for the emergence of the O104:H4 outbreak population.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-202921 (URN)10.1371/journal.pone.0063027 (DOI)000318852400020 ()
Available from: 2013-07-01 Created: 2013-07-01 Last updated: 2017-12-06Bibliographically approved
Almlöf, J. C., Lundmark, P., Lundmark, A., Ge, B., Maouche, S., Göring, H. H., . . . Syvänen, A.-C. (2012). Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression. PLoS ONE, 7(12), e52260
Open this publication in new window or tab >>Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e52260-Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
messenger RNA, allele specific gene expression analysis, article, blood donor, DNA flanking region, gene expression, gene frequency, gene mapping, genetic analysis, genetic association, genotype, genotyping expression analysis, human, human cell, intermethod comparison, monocyte, quantitative trait locus mapping, sample size, single nucleotide polymorphism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-195164 (URN)10.1371/journal.pone.0052260 (DOI)000313618800062 ()
Available from: 2013-02-22 Created: 2013-02-21 Last updated: 2017-12-06Bibliographically approved
Gunnarsson, R., Staaf, J., Jansson, M., Ottesen, A. M., Göransson, H., Liljedahl, U., . . . Rosenquist, R. (2008). Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia-A comparative study of four differently designed, high resolution microarray platforms. Genes, Chromosomes and Cancer, 47(8), 697-711
Open this publication in new window or tab >>Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia-A comparative study of four differently designed, high resolution microarray platforms
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2008 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 47, no 8, p. 697-711Article in journal (Refereed) Published
Abstract [en]

Screening for gene copy-number alterations (CNAs) has improved by applying genome-wide microarrays, where SNP arrays also allow analysis of loss of heterozygozity (LOH). We here analyzed 10 chronic lymphocytic leukemia (CLL) samples using four different high-resolution platforms: BAC arrays (32K), oligonucleotide arrays (185K, Agilent), and two SNP arrays (250K, Affymetrix and 317K, Illumina). Cross-platform comparison revealed 29 concordantly detected CNAs, including known recurrent alterations, which confirmed that all platforms are powerful tools when screening for large aberrations. However, detection of 32 additional regions present in 2-3 platforms illustrated a discrepancy in detection of small CNAs, which often involved reported copy-number variations. LOH analysis using dChip revealed concordance of mainly large regions, but showed numerous, small nonoverlapping regions and LOH escaping detection. Evaluation of baseline variation and copy-number ratio response showed the best performance for the Agilent platform and confirmed the robustness of BAC arrays. Accordingly, these platforms demonstrated a higher degree of platform-specific CNAs. The SNP arrays displayed higher technical variation, although this was compensated by high density of elements. Affymetrix detected a higher degree of CNAs compared to Illumina, while the latter showed a lower noise level and higher detection rate in the LOH analysis. Large-scale studies of genomic aberrations are now feasible, but new tools for LOH analysis are requested.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-16518 (URN)10.1002/gcc.20575 (DOI)000256874100006 ()18484635 (PubMedID)
Available from: 2008-05-27 Created: 2008-05-27 Last updated: 2017-12-08Bibliographically approved
Sigurdsson, S., Padyukov, L., Kurreeman, F. A. .., Liljedahl, U., Wiman, A.-C., Alfredsson, L., . . . Rönnblom, L. (2007). Association of a Haplotype in the Promoter Region of the Interferon Regulatory Factor 5 Gene With Rheumatoid Arthritis. Arthritis and Rheumatism, 56(7), 2202-2210
Open this publication in new window or tab >>Association of a Haplotype in the Promoter Region of the Interferon Regulatory Factor 5 Gene With Rheumatoid Arthritis
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2007 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, no 7, p. 2202-2210Article in journal (Refereed) Published
Abstract [en]

Objective. To determine whether genetic variants of the interferon regulatory factor 5 (IRF-5) and Tyk-2 genes are associated with rheumatoid arthritis (RA). Methods. Five single-nucleotide polymorphisms (SNPs) in IRF5 and 3 SNPs in Tyk2 were analyzed in a Swedish cohort of 1,530 patients with RA and 881 controls. A replication study was performed in a Dutch cohort of 387 patients with RA and 181 controls. All patient sera were tested for the presence of autoantibodies against cyclic citrullinated peptides (anti-CCP). Results. Four of the 5 SNPs located in the 5' region of IRF5 were associated with RA, while no association was observed with the Tyk2 SNPs. The minor alleles of 3 of the IRF5 SNPs, which were in linkage disequilibrium and formed a relatively common haplotype with a frequency of ∼0.33, appeared to confer protection against RA. Although these disease associations were seen in the entire patient group, they were mainly found in RA patients who were negative for anti-CCP. A suggestive association of IRF5 SNPs with anti-CCP-negative RA was also observed in the Dutch cohort. Conclusion. Given the fact that anti-CCP-negative RA differs from anti-CCP-positive RA with respect to genetic and environmental risk factor profiles, our results indicate that genetic variants of IRF5 contribute to a unique disease etiology and pathogenesis in anti-CCP-negative RA.

Keywords
Immunopathology, Diseases of the osteoarticular system, Inflammatory joint disease, Autoimmune disease, Cytokine, Chronic, Rheumatoid factor, Interferon, Promoter, Haplotype, Autoimmunity, Rheumatoid arthritis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-11887 (URN)10.1002/art.22704 (DOI)000248071600012 ()17599733 (PubMedID)
Available from: 2008-01-28 Created: 2008-01-28 Last updated: 2018-02-27Bibliographically approved
Kurland, L., Liljedahl, U. & Lind, L. (2005). Hypertension and SNP genotyping in antihypertensive treatment.. Cardiovasc Toxicol, 5(2), 133-42
Open this publication in new window or tab >>Hypertension and SNP genotyping in antihypertensive treatment.
2005 (English)In: Cardiovasc Toxicol, ISSN 1530-7905, Vol. 5, no 2, p. 133-42Article in journal (Other scientific) Published
Keywords
Animals, Antihypertensive Agents/*therapeutic use, Genotype, Humans, Hypertension/drug therapy/*genetics, Polymorphism; Single Nucleotide/*genetics, Research Support; Non-U.S. Gov't, Terminology
Identifiers
urn:nbn:se:uu:diva-80044 (URN)16046789 (PubMedID)
Available from: 2007-03-08 Created: 2007-03-08 Last updated: 2011-01-11
Kurland, L., Liljedahl, U., Karlsson, J., Kahan, T., Malmqvist, K., Melhus, H., . . . Lind, L. (2004). Angiotensinogen gene polymorphisms: relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial. American Journal of Hypertension, 17(1), 8-13
Open this publication in new window or tab >>Angiotensinogen gene polymorphisms: relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial
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2004 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 17, no 1, p. 8-13Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is important for the development of hypertension, and several antihypertensive drugs target this system. Our aim was to determine whether specific single nucleotide polymorphisms (SNPs) in RAAS genes were related to the blood pressure (BP) lowering effect of antihypertensive treatment. METHODS: Patients with mild to moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta(1)-adrenergic receptor blocker atenolol (n = 49) as monotherapy. A microarray-based minisequencing system was used to genotype 30 SNPs in seven genes in the RAAS. These polymorphisms were related to the antihypertensive response after 12 weeks treatment. RESULTS: The BP reductions were similar in the atenolol and the irbesartan groups. Presence of the angiotensinogen (AGT) -6A allele or the AGT 235T allele were both associated with the most pronounced systolic BP response to atenolol treatment (P =.001 when -6 AA+AG was compared with GG and P =.008 for presence of the 235T variant compared with 235 MM). CONCLUSIONS: We found that SNPs in the angiotensinogen gene were associated with the BP lowering response to atenolol. This study is limited by a relatively small sample size, and the results should therefore be viewed as preliminary. Despite this limitation, these results illustrate the potential of using SNP genotyping as a pharmacogenetic tool in antihypertensive treatment.

Keywords
Angiotensin II Type 1 Receptor Blockers, Angiotensinogen/*genetics, Antihypertensive Agents/*therapeutic use, Atenolol/*therapeutic use, Biphenyl Compounds/*therapeutic use, Blood Pressure, Double-Blind Method, Female, Genotype, Humans, Hypertension/complications/drug therapy/*genetics, Hypertrophy; Left Ventricular/etiology, Male, Middle Aged, Polymorphism; Single Nucleotide, Renin-Angiotensin System/*genetics, Research Support; Non-U.S. Gov't, Tetrazoles/*therapeutic use, Treatment Outcome
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-73304 (URN)10.1016/j.amjhyper.2003.09.009 (DOI)14700505 (PubMedID)
Available from: 2005-09-07 Created: 2005-09-07 Last updated: 2017-12-14Bibliographically approved
Liljedahl, U., Fredriksson, M., Dahlgren, A. & Syvänen, A.-C. (2004). Detecting imbalanced expression of SNP alleles by minisequencing on microarrays. BMC Biotechnology, 4(24), 1-10
Open this publication in new window or tab >>Detecting imbalanced expression of SNP alleles by minisequencing on microarrays
2004 (English)In: BMC Biotechnology, ISSN 1472-6750, E-ISSN 1472-6750, Vol. 4, no 24, p. 1-10Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Each of the human genes or transcriptional units is likely to contain single nucleotide polymorphisms that may give rise to sequence variation between individuals and tissues on the level of RNA. Based on recent studies, differential expression of the two alleles of heterozygous coding single nucleotide polymorphisms (SNPs) may be frequent for human genes. Methods with high accuracy to be used in a high throughput setting are needed for systematic surveys of expressed sequence variation. In this study we evaluated two formats of multiplexed, microarray based minisequencing for quantitative detection of imbalanced expression of SNP alleles. We used a panel of ten SNPs located in five genes known to be expressed in two endothelial cell lines as our model system.

RESULTS:

The accuracy and sensitivity of quantitative detection of allelic imbalance was assessed for each SNP by constructing regression lines using a dilution series of mixed samples from individuals of different genotype. Accurate quantification of SNP alleles by both assay formats was evidenced for by R2 values > 0.95 for the majority of the regression lines. According to a two sample t-test, we were able to distinguish 1-9% of a minority SNP allele from a homozygous genotype, with larger variation between SNPs than between assay formats. Six of the SNPs, heterozygous in either of the two cell lines, were genotyped in RNA extracted from the endothelial cells. The coefficient of variation between the fluorescent signals from five parallel reactions was similar for cDNA and genomic DNA. The fluorescence signal intensity ratios measured in the cDNA samples were compared to those in genomic DNA to determine the relative expression levels of the two alleles of each SNP. Four of the six SNPs tested displayed a higher than 1.4-fold difference in allelic ratios between cDNA and genomic DNA. The results were verified by allele-specific oligonucleotide hybridisation and minisequencing in a microtiter plate format.

CONCLUSIONS:

We conclude that microarray based minisequencing is an accurate and accessible tool for multiplexed screening for imbalanced allelic expression in multiple samples and tissues in parallel.

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-92628 (URN)10.1186/1472-6750-4-24 (DOI)000225233200001 ()15500681 (PubMedID)
Available from: 2005-02-18 Created: 2005-02-18 Last updated: 2017-12-14Bibliographically approved
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