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1.	Andersson, Anna, et al. (author) Gene expression signatures in childhood acute leukemias are largely unique and distinct from those of normal tissues and other malignancies. 2010 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 3 Journal article (peer-reviewed)abstract BACKGROUND: Childhood leukemia is characterized by the presence of balanced chromosomal translocations or by other structural or numerical chromosomal changes. It is well know that leukemias with specific molecular abnormalities display profoundly different global gene expression profiles. However, it is largely unknown whether such subtype-specific leukemic signatures are unique or if they are active also in non-hematopoietic normal tissues or in other human cancer types. METHODS: Using gene set enrichment analysis, we systematically explored whether the transcriptional programs in childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML) were significantly similar to those in different flow-sorted subpopulations of normal hematopoietic cells (n = 8), normal non-hematopoietic tissues (n = 22) or human cancer tissues (n = 13). RESULTS: This study revealed that e.g., the t(12;21) [ETV6-RUNX1] subtype of ALL and the t(15;17) [PML-RARA] subtype of AML had transcriptional programs similar to those in normal Pro-B cells and promyelocytes, respectively. Moreover, the 11q23/MLL subtype of ALL showed similarities with non-hematopoietic tissues. Strikingly however, most of the transcriptional programs in the other leukemic subtypes lacked significant similarity to approximately 100 gene sets derived from normal and malignant tissues. CONCLUSIONS: This study demonstrates, for the first time, that the expression profiles of childhood leukemia are largely unique, with limited similarities to transcriptional programs active in normal hematopoietic cells, non-hematopoietic normal tissues or the most common forms of human cancer. In addition to providing important pathogenetic insights, these findings should facilitate the identification of candidate genes or transcriptional programs that can be used as unique targets in leukemia.
2.	Heidenblad, Markus, et al. (author) Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors. 2008 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 1:Jan 31 Journal article (peer-reviewed)abstract ABSTRACT: BACKGROUND: Urothelial carcinoma (UC) is characterized by nonrandom chromosomal aberrations, varying from one or a few changes in early-stage and low-grade tumors, to highly rearranged karyotypes in muscle-invasive lesions. Recent array-CGH analyses have shed further light on the genomic changes underlying the neoplastic development of UC, and have facilitated the molecular delineation amplified and deleted regions to the level of specific candidate genes. In the present investigation we combine detailed genomic information with expression information to identify putative target genes for genomic amplifications. METHODS: We analyzed 38 urothelial carcinomas by whole-genome tiling resolution array-CGH and high density expression profiling to identify putative target genes in common genomic amplifications. When necessary expression profiling was complemented with Q-PCR of individual genes. RESULTS: Three genomic segments were frequently and exclusively amplified in high grade tumors; 1q23, 6p22 and 8q22, respectively. Detailed mapping of the 1q23 segment showed a heterogeneous amplification pattern and no obvious commonly amplified region. The 6p22 amplicon was defined by a 1.8 Mb core region present in all amplifications, flanked both distally and proximally by segments amplified to a lesser extent. By combining genomic profiles with expression profiles we could show that amplification of E2F3, CDKAL1, SOX4, and MBOAT1 as well as NUP153, AOF1, FAM8A1 and DEK in 6p22 was associated with increased gene expression. Amplification of the 8q22 segment was primarily associated with YWHAZ (14-3-3-zeta) and POLR2K over expression. The possible importance of the YWHA genes in the development of urothelial carcinomas was supported by another recurrent amplicon paralogous to 8q22, in 2p25, where increased copy numbers lead to enhanced expression of YWHAQ (14-3-3-theta). Homozygous deletions were identified at 10 different genomic locations, most frequently affecting CDKN2A/CDKN2B in 9p21 (32%). Notably, the latter occurred mutually exclusive with 6p22 amplifications. CONCLUSION: The presented data indicates 6p22 as a composite amplicon with more than one possible target gene. The data also suggests that amplification of 6p22 and homozygous deletions of 9p21 may have complementary roles. Furthermore, the analysis of paralogous regions that showed genomic amplification indicated altered expression of YWHA (14-3-3) genes as important events in the development of UC.
3.	Parikh, Hemang, et al. (author) Prioritizing genes for follow-up from genome wide association studies using information on gene expression in tissues relevant for type 2 diabetes mellitus 2009 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 2 Journal article (peer-reviewed)abstract Background: Genome-wide association studies (GWAS) have emerged as a powerful approach for identifying susceptibility loci associated with polygenetic diseases such as type 2 diabetes mellitus (T2DM). However, it is still a daunting task to prioritize single nucleotide polymorphisms (SNPs) from GWAS for further replication in different population. Several recent studies have shown that genetic variation often affects gene-expression at proximal (cis) as well as distal (trans) genomic locations by different mechanisms such as altering rate of transcription or splicing or transcript stability. Methods: To prioritize SNPs from GWAS, we combined results from two GWAS related to T2DM, the Diabetes Genetics Initiative (DGI) and the Wellcome Trust Case Control Consortium (WTCCC), with genome-wide expression data from pancreas, adipose tissue, liver and skeletal muscle of individuals with or without T2DM or animal models thereof to identify T2DM susceptibility loci. Results: We identified 1,170 SNPs associated with T2DM with P < 0.05 in both GWAS and 243 genes that were located in the vicinity of these SNPs. Out of these 243 genes, we identified 115 differentially expressed in publicly available gene expression profiling data. Notably five of them, IGF2BP2, KCNJ11, NOTCH2, TCF7L2 and TSPAN8, have subsequently been shown to be associated with T2DM in different populations. To provide further validation of our approach, we reversed the approach and started with 26 known SNPs associated with T2DM and related traits. We could show that 12 (57%) (HHEX, HNF1B, IGF2BP2, IRS1, KCNJ11, KCNQ1, NOTCH2, PPARG, TCF7L2, THADA, TSPAN8 and WFS1) out of 21 genes located in vicinity of these SNPs were showing aberrant expression in T2DM from the gene expression profiling studies. Conclusions: Utilizing of gene expression profiling data from different tissues of individuals with or without T2DM or animal models thereof is a powerful tool for prioritizing SNPs from WGAS for further replication studies.
4.	Plunkett, Jevon, et al. (author) Primate-specific evolution of noncoding element insertion into PLA2G4C and human preterm birth 2010 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 3 Journal article (peer-reviewed)abstract Background: The onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. We hypothesize that higher primate-specific gene evolution may lead to these differences and target genes involved in human preterm birth, an area of global health significance. Methods: We performed a comparative genomics screen of highly conserved noncoding elements and identified PLA2G4C, a phospholipase A isoform involved in prostaglandin biosynthesis as human accelerated. To examine whether this gene demonstrating primate-specific evolution was associated with birth timing, we genotyped and analyzed 8 common single nucleotide polymorphisms (SNPs) in PLA2G4C in US Hispanic (n = 73 preterm, 292 control), US White (n = 147 preterm, 157 control) and US Black (n = 79 preterm, 166 control) mothers. Results: Detailed structural and phylogenic analysis of PLA2G4C suggested a short genomic element within the gene duplicated from a paralogous highly conserved element on chromosome 1 specifically in primates. SNPs rs8110925 and rs2307276 in US Hispanics and rs11564620 in US Whites were significant after correcting for multiple tests (p < 0.006). Additionally, rs11564620 (Thr360Pro) was associated with increased metabolite levels of the prostaglandin thromboxane in healthy individuals (p = 0.02), suggesting this variant may affect PLA2G4C activity. Conclusions: Our findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.
5.	Staaf, Johan, et al. (author) Relation between smoking history and gene expression profiles in lung adenocarcinomas 2012 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 5 Journal article (peer-reviewed)abstract Background: Lung cancer is the worldwide leading cause of death from cancer. Tobacco usage is the major pathogenic factor, but all lung cancers are not attributable to smoking. Specifically, lung cancer in never-smokers has been suggested to represent a distinct disease entity compared to lung cancer arising in smokers due to differences in etiology, natural history and response to specific treatment regimes. However, the genetic aberrations that differ between smokers and never-smokers' lung carcinomas remain to a large extent unclear. Methods: Unsupervised gene expression analysis of 39 primary lung adenocarcinomas was performed using Illumina HT-12 microarrays. Results from unsupervised analysis were validated in six external adenocarcinoma data sets (n=687), and six data sets comprising normal airway epithelial or normal lung tissue specimens (n=467). Supervised gene expression analysis between smokers and never-smokers were performed in seven adenocarcinoma data sets, and results validated in the six normal data sets. Results: Initial unsupervised analysis of 39 adenocarcinomas identified two subgroups of which one harbored all never-smokers. A generated gene expression signature could subsequently identify never-smokers with 79-100% sensitivity in external adenocarcinoma data sets and with 76-88% sensitivity in the normal materials. A notable fraction of current/former smokers were grouped with never-smokers. Intriguingly, supervised analysis of never-smokers versus smokers in seven adenocarcinoma data sets generated similar results. Overlap in classification between the two approaches was high, indicating that both approaches identify a common set of samples from current/former smokers as potential never-smokers. The gene signature from unsupervised analysis included several genes implicated in lung tumorigenesis, immune-response associated pathways, genes previously associated with smoking, as well as marker genes for alveolar type II pneumocytes, while the best classifier from supervised analysis comprised genes strongly associated with proliferation, but also genes previously associated with smoking. Conclusions: Based on gene expression profiling, we demonstrate that never-smokers can be identified with high sensitivity in both tumor material and normal airway epithelial specimens. Our results indicate that tumors arising in never-smokers, together with a subset of tumors from smokers, represent a distinct entity of lung adenocarcinomas. Taken together, these analyses provide further insight into the transcriptional patterns occurring in lung adenocarcinoma stratified by smoking history.
6.	Thorell, Kaisa, 1983, et al. (author) Verification of genes differentially expressed in neuroblastoma tumours : A study of potential tumour suppressor genes 2009 In: BMC Medical Genomics. - : BioMed Central (BMC). - 1755-8794. ; 2 Journal article (peer-reviewed)abstract Background: One of the most striking features of the childhood malignancy neuroblastoma (NB) is its clinical heterogeneity. Although there is a great need for better clinical and biological markers to distinguish between tumours with different severity and to improve treatment, no clear-cut prognostic factors have been found. Also, no major NB tumour suppressor genes have been identified.Methods: In this study we performed expression analysis by quantitative real-time PCR (QPCR) on primary NB tumours divided into two groups, of favourable and unfavourable outcome respectively. Candidate genes were selected on basis of lower expression in unfavourable tumour types compared to favourables in our microarray expression analysis. Selected genes were studied in two steps: (1) using TaqMan Low Density Arrays (TLDA) targeting 89 genes on a set of 12 NB tumour samples, and (2) 12 genes were selected from the TLDA analysis for verification using individual TaqMan assays in a new set of 13 NB tumour samples.Results: By TLDA analysis, 81 out of 87 genes were found to be significantly differentially expressed between groups, of which 14 have previously been reported as having an altered gene expression in NB. In the second verification round, seven out of 12 transcripts showed significantly lower expression in unfavourable NB tumours, ATBF1, CACNA2D3, CNTNAP2, FUSIP1, GNB1, SLC35E2, and TFAP2B. The gene that showed the highest fold change in the TLDA analysis, POU4F2, was investigated for epigenetic changes (CpG methylation) and mutations in order to explore the cause of the differential expression. Moreover, the fragile site gene CNTNAP2 that showed the largest fold change in verification group 2 was investigated for structural aberrations by copy number analysis. However, the analyses of POU4F2 and CNTNAP2 showed no genetic alterations that could explain a lower expression in unfavourable NB tumours.Conclusion: Through two steps of verification, seven transcripts were found to significantly discriminate between favourable and unfavourable NB tumours. Four of the transcripts, CACNA2D3, GNB1, SLC35E2, and TFAP2B, have been observed in previous microarray studies, and are in this study independently verified. Our results suggest these transcripts to be markers of malignancy, which could have a potential usefulness in the clinic.
7.	Sboner, Andrea, et al. (author) Molecular sampling of prostate cancer: a dilemma for predicting disease progression 2010 In: BMC Medical Genomics. - London, United Kingdom : BioMed Central. - 1755-8794. ; 3:8 Journal article (peer-reviewed)abstract Background: Current prostate cancer prognostic models are based on pre-treatment prostate specific antigen (PSA) levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict disease progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models. Methods: We analyzed a Swedish Watchful Waiting cohort with up to 30 years of clinical follow up using a novel method for gene expression profiling. This cDNA-mediated annealing, selection, ligation, and extension (DASL) method enabled the use of formalin-fixed paraffin-embedded transurethral resection of prostate (TURP) samples taken at the time of the initial diagnosis. We determined the expression profiles of 6100 genes for 281 men divided in two extreme groups: men who died of prostate cancer and men who survived more than 10 years without metastases (lethals and indolents, respectively). Several statistical and machine learning models using clinical and molecular features were evaluated for their ability to distinguish lethal from indolent cases. Results: Surprisingly, none of the predictive models using molecular profiles significantly improved over models using clinical variables only. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes is widespread in prostate cancer as compared to other types of tumors. Conclusions: The determination of the molecularly dominant tumor nodule may be limited by sampling at time of initial diagnosis, may not be present at time of initial diagnosis, or may occur as the disease progresses making the development of molecular biomarkers for prostate cancer progression challenging.
8.	Beck, Dominik, et al. (author) Integrative analysis of next generation sequencing for small non-coding RNAs and transcriptional regulation in Myelodysplastic Syndromes 2011 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 4:19, s. 1-16 Journal article (peer-reviewed)abstract BackgroundMyelodysplastic Syndromes (MDSS) are pre-leukemic disorders with increasing incident rates worldwide, but very limited treatment options. Little is known about small regulatory RNAs and how they contribute to pathogenesis, progression and transcriptome changes in MDS.MethodsPatients' primary marrow cells were screened for short RNAs (RNA-seq) using next generation sequencing. Exon arrays from the same cells were used to profile gene expression and additional measures on 98 patients obtained. Integrative bioinformatics algorithms were proposed, and pathway and ontology analysis performed.ResultsIn low-grade MDS, observations implied extensive post-transcriptional regulation via microRNAs (miRNA) and the recently discovered Piwi interacting RNAs (piRNA). Large expression differences were found for MDS-associated and novel miRNAs, including 48 sequences matching to miRNA star (miRNA) motifs. The detected species were predicted to regulate disease stage specific molecular functions and pathways, including apoptosis and response to DNA damage. In high-grade MDS, results suggested extensive post-translation editing via transfer RNAs (tRNAs), providing a potential link for reduced apoptosis, a hallmark for this disease stage. Bioinformatics analysis confirmed important regulatory roles for MDS linked miRNAs and TFs, and strengthened the biological significance of miRNA. The "RNA polymerase II promoters" were identified as the tightest controlled biological function. We suggest their control by a miRNA dominated feedback loop, which might be linked to the dramatically different miRNA amounts seen between low and high-grade MDS.DiscussionThe presented results provide novel findings that build a basis of further investigations of diagnostic biomarkers, targeted therapies and studies on MDS pathogenesis.
9.	Bysani, Madhu Sudhan Reddy, et al. (author) ChIP-seq in steatohepatitis and normal liver tissue identifies candidate disease mechanisms related to progression to cancer 2013 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 6, s. 50- Journal article (peer-reviewed)abstract Background: Steatohepatitis occurs in alcoholic liver disease and may progress to liver cirrhosis and hepatocellular carcinoma. Its molecular pathogenesis is to a large degree unknown. Histone modifications play a key role in transcriptional regulations as marks for silencing and activation of gene expression and as marks for functional elements. Many transcription factors (TFs) are crucial for the control of the genes involved in metabolism, and abnormality in their function may lead to disease. Methods: We performed ChIP-seq of the histone modifications H3K4me1, H3K4me3 and H3K27ac and a candidate transcription factor (USF1) in liver tissue from patients with steatohepatitis and normal livers and correlated results to mRNA-expression and genotypes. Results: We found several regions that are differentially enriched for histone modifications between disease and normal tissue, and qRT-PCR results indicated that the expression of the tested genes strongly correlated with differential enrichment of histone modifications but is independent of USF1 enrichment. By gene ontology analysis of differentially modified genes we found many disease associated genes, some of which had previously been implicated in the etiology of steatohepatitis. Importantly, the genes associated to the strongest histone peaks in the patient were over-represented in cancer specific pathways suggesting that the tissue was on a path to develop to cancer, a common complication to the disease. We also found several novel SNPs and GWAS catalogue SNPs that are candidates to be functional and therefore needs further study. Conclusion: In summary we find that analysis of chromatin features in tissue samples provides insight into disease mechanisms.
10.	Clancy, Trevor, et al. (author) Immunological network signatures of cancer progression and survival. 2011 In: BMC medical genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 4:1 Journal article (peer-reviewed)abstract ABSTRACT: BACKGROUND: The immune contribution to cancer progression is complex and difficult to characterize. For example in tumors, immune gene expression is detected from the combination of normal, tumor and immune cells in the tumor microenvironment. Profiling the immune component of tumors may facilitate the characterization of the poorly understood roles immunity plays in cancer progression. However, the current approaches to analyze the immune component of a tumor rely on incomplete identification of immune factors. METHODS: To facilitate a more comprehensive approach, we created a ranked immunological relevance score for all human genes, developed using a novel strategy that combines text mining and information theory. We used this score to assign an immunological grade to gene expression profiles, and thereby quantify the immunological component of tumors. This immunological relevance score was benchmarked against existing manually curated immune resources as well as high-throughput studies. To further characterize immunological relevance for genes, the relevance score was charted against both the human interactome and cancer information, forming an expanded interactome landscape of tumor immunity. We applied this approach to expression profiles in melanomas, thus identifying and grading their immunological components, followed by identification of their associated protein interactions. RESULTS: The power of this strategy was demonstrated by the observation of early activation of the adaptive immune response and the diversity of the immune component during melanoma progression. Furthermore, the genome-wide immunological relevance score classified melanoma patient groups, whose immunological grade correlated with clinical features, such as immune phenotypes and survival. CONCLUSIONS: The assignment of a ranked immunological relevance score to all human genes extends the content of existing immune gene resources and enriches our understanding of immune involvement in complex biological networks. The application of this approach to tumor immunity represents an automated systems strategy that quantifies the immunological component in complex disease. In so doing, it stratifies patients according to their immune profiles, which may lead to effective computational prognostic and clinical guides.
11.	Jiao, Hong, et al. (author) Genome wide association study identifies KCNMA1 contributing to human obesity 2011 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 4, s. 51- Journal article (peer-reviewed)abstract Background: Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity. Methods: We performed a GWA analysis in 164 morbidly obese subjects (BMI: body mass index > 40 kg/m(2)) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for 14 adults. Results: Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830G and BDNF rs988712G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830G with P = 2.82 x 10(-10) and an odds ratio (OR) based on cases vs controls of 1.26 [95% C. I. 1.12-1.41] and for BDNF rs988712G with P = 5.2 x 10(-17) and an OR of 1.36 [95% C. I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P = 0.0001) and fat cell (P = 0.04) expression of KCNMA1 was increased in obesity. Conclusions: We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.
12.	Jonsson, Lina, 1982, et al. (author) Mutation screening of melatonin-related genes in patients with autism spectrum disorders. 2010 In: BMC medical genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 3 Journal article (peer-reviewed)abstract BACKGROUND: One consistent finding in autism spectrum disorders (ASD) is a decreased level of the pineal gland hormone melatonin and it has recently been demonstrated that this decrease to a large extent is due to low activity of the acetylserotonin O-methyltransferase (ASMT), the last enzyme in the melatonin synthesis pathway. Moreover, mutations in the ASMT gene have been identified, including a splice site mutation, that were associated with low ASMT activity and melatonin secretion, suggesting that the low ASMT activity observed in autism is, at least partly, due to variation within the ASMT gene. METHODS: In the present study, we have investigated all the genes involved in the melatonin pathway by mutation screening of AA-NAT (arylalkylamine N-acetyltransferase), ASMT, MTNR1A, MTNR1B (melatonin receptor 1A and 1B) and GPR50 (G protein-coupled receptor 50), encoding both synthesis enzymes and the three main receptors of melatonin, in 109 patients with autism spectrum disorders (ASD). A cohort of 188 subjects from the general population was used as a comparison group and was genotyped for the variants identified in the patient sample. RESULTS: Several rare variants were identified in patients with ASD, including the previously reported splice site mutation in ASMT (IVS5+2T>C). Of the variants affecting protein sequence, only the V124I in the MTNR1B gene was absent in our comparison group. However, mutations were found in upstream regulatory regions in three of the genes investigated, ASMT, MTNR1A, and MTNR1B. CONCLUSIONS: Our report of another ASD patient carrying the splice site mutation IVS5+2T>C, in ASMT further supports an involvement of this gene in autism. Moreover, our results also suggest that other melatonin related genes might be interesting candidates for further investigation in the search for genes involved in autism spectrum disorders and related neurobehavioral phenotypes. However, further studies of the novel variants identified in this study are warranted to shed light on their potential role in the pathophysiology of these disorders.
13.	Jylhava, J, et al. (author) Identification of a prognostic signature for old-age mortality by integrating genome-wide transcriptomic data with the conventional predictors: the Vitality 90+ Study 2014 In: BMC medical genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 7, s. 54- Journal article (peer-reviewed)
14.	Kutlu, Burak, et al. (author) Detailed transcriptome atlas of the pancreatic beta cell 2009 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 2, s. 3- Journal article (peer-reviewed)abstract BACKGROUND: Gene expression patterns provide a detailed view of cellular functions. Comparison of profiles in disease vs normal conditions provides insights into the processes underlying disease progression. However, availability and integration of public gene expression datasets remains a major challenge. The aim of the present study was to explore the transcriptome of pancreatic islets and, based on this information, to prepare a comprehensive and open access inventory of insulin-producing beta cell gene expression, the Beta Cell Gene Atlas (BCGA). METHODS: We performed Massively Parallel Signature Sequencing (MPSS) analysis of human pancreatic islet samples and microarray analyses of purified rat beta cells, alpha cells and INS-1 cells, and compared the information with available array data in the literature. RESULTS: MPSS analysis detected around 7600 mRNA transcripts, of which around a third were of low abundance. We identified 2000 and 1400 transcripts that are enriched/depleted in beta cells compared to alpha cells and INS-1 cells, respectively. Microarray analysis identified around 200 transcription factors that are differentially expressed in either beta or alpha cells. We reanalyzed publicly available gene expression data and integrated these results with the new data from this study to build the BCGA. The BCGA contains basal (untreated conditions) gene expression level estimates in beta cells as well as in different cell types in human, rat and mouse pancreas. Hierarchical clustering of expression profile estimates classify cell types based on species while beta cells were clustered together. CONCLUSION: Our gene atlas is a valuable source for detailed information on the gene expression distribution in beta cells and pancreatic islets along with insulin producing cell lines. The BCGA tool, as well as the data and code used to generate the Atlas are available at the T1Dbase website (T1DBase.org).
15.	Martijn, Cécile, et al. (author) Effect of methylene blue on the genomic response to reperfusion injury induced by cardiac arrest and cardiopulmonary resuscitation in porcine brain 2010 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 3, s. 27- Journal article (peer-reviewed)abstract Background: Cerebral ischemia/reperfusion injury is a common secondary effect of cardiac arrest which is largely responsible for postresuscitative mortality. Therefore development of therapies which restore and protect the brain function after cardiac arrest is essential. Methylene blue (MB) has been experimentally proven neuroprotective in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. However, no comprehensive analyses have been conducted at gene expression level. Methods: Pigs underwent either untreated cardiac arrest (CA) or CA with subsequent cardiopulmonary resuscitation (CPR) accompanied with an infusion of saline or an infusion of saline with MB. Genome-wide transcriptional profiling using the Affymetrix porcine microarray was performed to 1) gain understanding of delayed neuronal death initiation in porcine brain during ischemia and after 30, 60 and 180 min following reperfusion, and 2) identify the mechanisms behind the neuroprotective effect of MB after ischemic injury (at 30, 60 and 180 min). Results: Our results show that restoration of spontaneous circulation (ROSC) induces major transcriptional changes related to stress response, inflammation, apoptosis and even cytoprotection. In contrast, the untreated ischemic and anoxic insult affected only few genes mainly involved in intra-/extracellular ionic balance. Furthermore, our data show that the neuroprotective role of MB is diverse and fulfilled by regulation of the expression of soluble guanylate cyclase and biological processes accountable for inhibition of apoptosis, modulation of stress response, neurogenesis and neuroprotection. Conclusions: Our results support that MB could be a valuable intervention and should be investigated as a therapeutic agent against neural damage associated with I/R injury induced by cardiac arrest.
16.	Nookaew, Intawat, 1977, et al. (author) Transcriptome signatures in Helicobacter pylori-infected mucosa identifies acidic mammalian chitinase loss as a corpus atrophy marker 2013 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 6:41 Journal article (peer-reviewed)abstract The majority of gastric cancer cases are believed to be caused by chronic infection with the bacterium Helicobacter pylori, and atrophic corpus gastritis is a predisposing condition to gastric cancer development. We aimed to increase understanding of the molecular details of atrophy by performing a global transcriptome analysis of stomach tissue. Biopsies from patients with different stages of H. pylori infection were taken from both the antrum and corpus mucosa and analyzed on microarrays. The stages included patients without current H. pylori infection, H. pylori-infected without corpus atrophy and patients with current or past H. pylori-infection with corpus-predominant atrophic gastritis. Using clustering and integrated analysis, we found firm evidence for antralization of the corpus mucosa of atrophy patients. This antralization harbored gain of gastrin expression, as well as loss of expression of corpus-related genes, such as genes associated with acid production, energy metabolism and blood clotting. The analyses provided detailed molecular evidence for simultaneous intestinal metaplasia (IM) and spasmolytic polypeptide expressing metaplasia (SPEM) in atrophic corpus tissue. Finally, acidic mammalian chitinase, a chitin-degrading enzyme produced by chief cells, was shown to be strongly down-regulated in corpus atrophy. Transcriptome analysis revealed several gene groups which are related to development of corpus atrophy, some of which were increased also in H. pylori-infected non-atrophic patients. Furthermore, loss of acidic chitinase expression is a promising marker for corpus atrophy.
17.	Peri, Suraj, et al. (author) Defining the genomic signature of the parous breast 2012 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 5, s. 46- Journal article (peer-reviewed)abstract Background: It is accepted that a woman's lifetime risk of developing breast cancer after menopause is reduced by early full term pregnancy and multiparity. This phenomenon is thought to be associated with the development and differentiation of the breast during pregnancy.Methods: In order to understand the underlying molecular mechanisms of pregnancy induced breast cancer protection, we profiled and compared the transcriptomes of normal breast tissue biopsies from 71 parous (P) and 42 nulliparous (NP) healthy postmenopausal women using Affymetrix Human Genome U133 Plus 2.0 arrays. To validate the results, we performed real time PCR and immunohistochemistry.Results: We identified 305 differentially expressed probesets (208 distinct genes). Of these, 267 probesets were up- and 38 down-regulated in parous breast samples; bioinformatics analysis using gene ontology enrichment revealed that up-regulated genes in the parous breast represented biological processes involving differentiation and development, anchoring of epithelial cells to the basement membrane, hemidesmosome and cell-substrate junction assembly, mRNA and RNA metabolic processes and RNA splicing machinery. The down-regulated genes represented biological processes that comprised cell proliferation, regulation of IGF-like growth factor receptor signaling, somatic stem cell maintenance, muscle cell differentiation and apoptosis.Conclusions: This study suggests that the differentiation of the breast imprints a genomic signature that is centered in the mRNA processing reactome. These findings indicate that pregnancy may induce a safeguard mechanism at post-transcriptional level that maintains the fidelity of the transcriptional process.
18.	Smith, R, et al. (author) Novel transcriptional profile in wrist muscles from cerebral palsy patients 2009 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 2, s. 44- Journal article (peer-reviewed)abstract Background: Cerebral palsy (CP) is an upper motor neuron disease that results in a progressive movement disorder. Secondary to the neurological insult, muscles from CP patients often become spastic. Spastic muscle is characterized by an increased resistance to stretch, but often develops the further complication of contracture which represents a prominent disability in children with CP. This study's purpose is to characterize alterations of spastic muscle on the transcriptional level. Increased knowledge of spastic muscle may lead to novel therapies to improve the quality of life for children with CP. Method: The transcriptional profile of spastic muscles were defined in children with cerebral palsy and compared to control patients using Affymetrix U133A chips. Expression data were verified using quantitative-PCR (QPCR) and validated with SDS-PAGE for select genes. Significant genes were determined using a 2 x 2 ANOVA and results required congruence between 3 preprocessing algorithms. Results: CP patients clustered independently and 205 genes were significantly altered, covering a range of cellular processes. Placing gene expression in the context of physiological pathways, the results demonstrated that spastic muscle in CP adapts transcriptionally by altering extracellular matrix, fiber type, and myogenic potential. Extracellular matrix adaptations occur primarily in the basal lamina although there is increase in fibrillar collagen components. Fiber type is predominately fast compared to normal muscle as evidenced by contractile gene isoforms and decrease in oxidative metabolic gene transcription, despite a paradoxical increased transcription of slow fiber pathway genes. We also found competing pathways of fiber hypertrophy with an increase in the anabolic IGF1 gene in parallel with a paradoxical increase in myostatin, a gene responsible for stopping muscle growth. We found evidence that excitation-contraction coupling genes are altered in muscles from patients with CP and may be a significant component of disease. Conclusion: This is the first transcriptional profile performed on spastic muscle of CP patients and these adaptations were not characteristic of those observed in other disease states such as Duchenne muscular dystrophy and immobilization-induced muscle atrophy. Further research is required to understand the mechanism of muscle adaptation to this upper motor neuron lesion that could lead to the development of innovative therapies.
19.	Lazar, Vladimir, et al. (author) Integrated molecular portrait of non-small cell lung cancers 2013 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 6:1, s. 53- Journal article (peer-reviewed)abstract Background: Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods: Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results: At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of similar to 800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions: Integrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.
20.	Arora, Geeti, et al. (author) Association between genetic risk variants and glucose intolerance during pregnancy in north Indian women 2018 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 11 Journal article (peer-reviewed)abstract Background Gestational diabetes (GDM) is a more common problem in India than in many other parts of the world but it is not known whether this is due to unique environmental factors or a unique genetic background. To address this question we examined whether the same genetic variants associated with GDM and Type 2 Diabetes (T2D) in Caucasians also were associated with GDM in North Indian women. Methods Five thousand one hundred pregnant women of gestational age 24–28 weeks from Punjab were studied by a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed by both WHO1999 and 2013 criteria. 79 single nucleotide polymorphisms (SNPs) previously associated with T2D and glycemic traits (12 of them also with GDM) and 6 SNPs from previous T2D associations based on Indian population (some also with European) were genotyped on a Sequenom platform or using Taqman assays in DNA from 4018 women. Results In support of previous findings in Caucasian GDM, SNPs at KCJN11 and GRB14 loci were nominally associated with GDM1999 risk in Indian women (both p = 0.02). Notably, T2D risk alleles of the variant rs1552224 near CENTD2, rs11708067 in ADCY5 and rs11605924 in CRY2 genes associated with protection from GDM regardless of criteria applied (p < 0.025). SNPs rs7607980 near COBLL1 (p = 0.0001), rs13389219 near GRB14 (p = 0.026) and rs10423928 in the GIPR gene (p = 0.012) as well as the genetic risk score (GRS) for these previously shown insulin resistance loci here associated with insulin resistance defined by HOMA2-IR and showed a trend towards GDM. GRS comprised of 3 insulin secretion loci here associated with insulin secretion but not GDM. Conclusions GDM in women from Punjab in Northern India shows a genetic component, seemingly driven by insulin resistance and secretion and partly shared with GDM in other parts of the world. Most previous T2D loci discovered in European studies did not associate with GDM in North India, indicative of different genetic etiology or alternately, differences in the linkage disequilibrium (LD) structure between populations in which the associated SNPs were identified and Northern Indian women. Interestingly some T2D risk variants were in fact indicative of being protective for GDM in these Indian women.
21.	Boström, Adrian E., et al. (author) Longitudinal genome-wide methylation study of Roux-en-Y gastric bypass patients reveals novel CpG sites associated with essential hypertension 2016 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 9 Journal article (peer-reviewed)abstract Background: Essential hypertension is a significant risk factor for cardiovascular diseases. Emerging research suggests a role of DNA methylation in blood pressure physiology. We aimed to investigate epigenetic associations of promoter related CpG sites to essential hypertension in a genome-wide methylation approach. Methods: The genome-wide methylation pattern in whole blood was measured in 11 obese patients before and six months after Roux-en-Y gastric bypass surgery using the Illumina 450 k beadchip. CpG sites located within 1500 bp of the transcriptional start site of adjacent genes were included in our study, resulting in 124 199 probes investigated in the subsequent analysis. Percent changes in methylation states and SBP measured before and six months after surgery were calculated. These parameters were correlated to each other using the Spearman's rank correlation method (Edgeworth series approximation). To further investigate the detected relationship between candidate CpG sites and systolic blood pressure levels, binary logistic regression analyses were performed in a larger and independent cohort of 539 individuals aged 19-101 years to elucidate a relationship between EH and the methylation state in candidate CpG sites. Results: We identified 24 promoter associated CpG sites that correlated with change in SBP after RYGB surgery (p < 10-16). Two of these CpG loci (cg00875989, cg09134341) were significantly hypomethylated in dependency of EH (p < 10-03). These results were independent of age, BMI, ethnicity and sex. Conclusions: The identification of these novel CpG sites may contribute to a further understanding of the epigenetic regulatory mechanisms underlying the development of essential hypertension.
22.	Engvall, Marie, et al. (author) Detection of leukemia gene fusions by targeted RNA-sequencing in routine diagnostics 2020 In: BMC Medical Genomics. - : BMC. - 1755-8794. ; 13:1 Journal article (peer-reviewed)abstract Background We have evaluated an NGS-based method to detect recurrent gene fusions of diagnostic and prognostic importance in hematological malignancies. Our goal was to achieve a highly specific assay with a simple workflow, short turnaround time and low cost. Method The assay uses a commercially available anchored multiplex PCR panel for target enrichment and library preparation, followed by sequencing using a MiSeq instrument. The panel includes all recurrent gene fusions in AML and ALL and is designed to detect gene-specific fusions without prior knowledge of the partner sequence or specific break points. Diagnostic RNA samples from 27 cases with hematological malignancies encompassing 23 different transcript variants were analyzed. In addition, 12 cases from a validation cohort were assessed. Result All known fusion transcripts were identified with a high degree of confidence, with a large number of reads covering the breakpoints. Importantly, we could identify gene fusions where conventional methods had failed due to cryptic rearrangements or rare fusion partners. The newly-identified fusion partners were verified by RT-PCR and transcript-specific qPCR was designed for patient-specific follow-up. In addition, 12 cases were correctly assessed in a blind test, without prior knowledge of molecular cytogenetics or diagnosis. Conclusion In summary, our results demonstrate that targeted RNA sequencing using anchored multiplex PCR can be implemented in a clinical laboratory for the detection of recurrent and rare gene fusions in hematological diagnostic samples.
23.	Eriksson, Pontus, et al. (author) Molecular subtypes of urothelial carcinoma are defined by specific gene regulatory systems. 2015 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 8:1 Journal article (peer-reviewed)abstract Molecular stratification of bladder cancer has revealed gene signatures differentially expressed across tumor subtypes. While these signatures provide important insights into subtype biology, the transcriptional regulation that governs these signatures is not well characterized.
24.	Friedrich, Stefanie, et al. (author) Fusion transcript detection using spatial transcriptomics 2020 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 13:1 Journal article (peer-reviewed)abstract Background: Fusion transcripts are involved in tumourigenesis and play a crucial role in tumour heterogeneity, tumour evolution and cancer treatment resistance. However, fusion transcripts have not been studied at high spatial resolution in tissue sections due to the lack of full-length transcripts with spatial information. New high-throughput technologies like spatial transcriptomics measure the transcriptome of tissue sections on almost single-cell level. While this technique does not allow for direct detection of fusion transcripts, we show that they can be inferred using the relative poly(A) tail abundance of the involved parental genes.Method: We present a new method STfusion, which uses spatial transcriptomics to infer the presence and absence of poly(A) tails. A fusion transcript lacks a poly(A) tail for the 5 ' gene and has an elevated number of poly(A) tails for the 3 ' gene. Its expression level is defined by the upstream promoter of the 5 ' gene. STfusion measures the difference between the observed and expected number of poly(A) tails with a novel C-score.Results: We verified the STfusion ability to predict fusion transcripts on HeLa cells with known fusions. STfusion and C-score applied to clinical prostate cancer data revealed the spatial distribution of the cis-SAGeSLC45A3-ELK4in 12 tissue sections with almost single-cell resolution. The cis-SAGe occurred in disease areas, e.g. inflamed, prostatic intraepithelial neoplastic, or cancerous areas, and occasionally in normal glands.Conclusions: STfusion detects fusion transcripts in cancer cell line and clinical tissue data, and distinguishes chimeric transcripts from chimeras caused by trans-splicing events. With STfusion and the use of C-scores, fusion transcripts can be spatially localised in clinical tissue sections on almost single cell level.
25.	Friedrich, Stefanie, et al. (author) MetaCNV-a consensus approach to infer accurate copy numbers from low coverage data 2020 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 13 Journal article (peer-reviewed)abstract Background: The majority of copy number callers requires high read coverage data that is often achieved with elevated material input, which increases the heterogeneity of tissue samples. However, to gain insights into smaller areas within a tissue sample, e.g. a cancerous area in a heterogeneous tissue sample, less material is used for sequencing, which results in lower read coverage. Therefore, more focus needs to be put on copy number calling that is sensitive enough for low coverage data.Results: We present MetaCNV, a copy number caller that infers reliable copy numbers for human genomes with a consensus approach. MetaCNV specializes in low coverage data, but also performs well on normal and high coverage data. MetaCNV integrates the results of multiple copy number callers and infers absolute and unbiased copy numbers for the entire genome. MetaCNV is based on a meta-model that bypasses the weaknesses of current calling models while combining the strengths of existing approaches. Here we apply MetaCNV based on ReadDepth, SVDetect, and CNVnator to real and simulated datasets in order to demonstrate how the approach improves copy number calling.Conclusions: MetaCNV, available at https://bitbucket.org/sonnhammergroup/metacnv, provides accurate copy number prediction on low coverage data and performs well on high coverage data.
26.	Galatenko, Vladimir V, et al. (author) Cumulative prognostic power of laminin genes in colorectal cancer. 2018 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 11:Suppl 1 Journal article (peer-reviewed)abstract BACKGROUND: Laminins are a major family of extracellular matrix proteins and the main component of basement membranes. Laminins are involved in many if not all stages of cancer progression, and expression of laminin genes has prognostic value in various types of cancer, including colorectal. Only single laminin genes or components of a single laminin trimer with significant differential expression have been regarded as potential biomarkers to date.RESULTS: Here we compared prognostic power of classifiers constructed from sets of laminin genes with that of any single laminin gene. The analysis showed that cumulative prognostic power of sets of laminin genes was higher and was achieved already with pairs and triples of the genes. Interestingly, components of the pairs and the triples did not belong to any known laminin trimer, but, taken together with the gene weights, suggested higher LAMA4/LAMA5 expression ratio in patients with poor prognosis.CONCLUSIONS: Analysis of the laminin expression profile rather than expression of the single genes or components of laminin trimers is useful for colorectal cancer prognosis in patients. High LAMA4/LAMA5 ratio is associated with increased permeability of basement membranes suggesting that basement membranes produced by colorectal tumors might be an important hindrance to their own dissemination in patients.
27.	Glicksberg, BS, et al. (author) Correction to: Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits 2019 In: BMC medical genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 12:1, s. 154- Journal article (peer-reviewed)abstract .
28.	Glicksberg, Benjamin S., et al. (author) Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits 2019 In: BMC Medical Genomics. - : BMC. - 1755-8794. ; 12 Journal article (peer-reviewed)abstract BackgroundGenetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.ResultsWe identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.ConclusionIn sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.
29.	Hedman, Åsa K., et al. (author) DNA methylation patterns associated with oxidative stress in an ageing population 2016 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 9 Journal article (peer-reviewed)abstract Background: Oxidative stress has been related to type 2 diabetes (T2D) and cardiovascular disease (CVD), the leading global cause of death. Contributions of environmental factors such as oxidative stress on complex traits and disease may be partly mediated through changes in epigenetic marks (e.g. DNA methylation). Studies relating differential methylation with intermediate phenotypes and disease endpoints may be useful in identifying additional candidate genes and mechanisms involved in disease. Methods: To investigate the role of epigenetic variation in oxidative stress marker levels and subsequent development of CVD and T2D, we performed analyses of genome-wide DNA methylation in blood, ten markers of oxidative stress (total glutathione [TGSH], reduced glutathione [GSH], oxidised glutathione [GSSG], GSSG to GSH ratio, homocysteine [HCY], oxidised low-density lipoprotein (oxLDL), antibodies against oxLDL [OLAB], conjugated dienes [CD], baseline conjugated dienes [BCD]-LDL and total antioxidant capacity [TAOC]) and incident disease in up to 966 age-matched individuals. Results: In total, we found 66 cytosine-guanine (CpG) sites associated with one or more oxidative stress markers (false discovery rate [FDR] <0.05). These sites were enriched in regulatory regions of the genome. Genes annotated to CpG sites showed enrichment in annotation clusters relating to phospho-metabolism and proteins with pleckstrin domains. We investigated the contribution of oxidative stress-associated CpGs to development of cardiometabolic disease. Methylation variation at CpGs in the 3'-UTR of HIST1H4D (cg08170869; histone cluster 1, H4d) and in the body of DVL1 (cg03465880; dishevelled-1) were associated with incident T2D events during 10 years of follow-up (all permutation p-values < 0.01), indicating a role of epigenetic regulation in oxidative stress processes leading to development or progression of diabetes. Methylation QTL (meQTL) analysis showed significant associations with genetic sequence variants in cis at 28 (42%) of oxidative stress phenotype-associated sites (FDR < 0.05). Integrating cis-meQTLs with genotype-phenotype associations indicated that genetic effects on oxidative stress phenotype at one locus (cg07547695; BCL2L11) may be mediated through DNA methylation. Conclusions: In conclusion, we report novel associations of DNA methylation with oxidative stress, some of which also show evidence of a relation with T2D incidence.
30.	Klar, Joakim, PhD, 1974-, et al. (author) Whole genome sequencing of familial isolated oesophagus atresia uncover shared structural variants 2020 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 13:1 Journal article (peer-reviewed)abstract BackgroundOesophageal atresia (OA) is a life-threatening developmental defect characterized by a lost continuity between the upper and lower oesophagus. The most common form is a distal connection between the trachea and the oesophagus, i.e. a tracheoesophageal fistula (TEF). The condition may be part of a syndrome or occurs as an isolated feature. The recurrence risk in affected families is increased compared to the population-based incidence suggesting contributing genetic factors.MethodsTo gain insight into gene variants and genes associated with isolated OA we conducted whole genome sequencing on samples from three families with recurrent cases affected by congenital and isolated TEF.ResultsWe identified a combination of single nucleotide variants (SNVs), splice site variants (SSV) and structural variants (SV) annotated to altogether 100 coding genes in the six affected individuals.ConclusionThis study highlights rare SVs among candidate gene variants in our individuals with OA and provides a gene framework for further investigations of genetic factors behind this malformation.
31.	Kleftogiannis, Dimitrios, et al. (author) Identification of single nucleotide variants using position-specific error estimation in deep sequencing data. 2019 In: BMC medical genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 12:1 Journal article (peer-reviewed)abstract Targeted deep sequencing is a highly effective technology to identify known and novel single nucleotide variants (SNVs) with many applications in translational medicine, disease monitoring and cancer profiling. However, identification of SNVs using deep sequencing data is a challenging computational problem as different sequencing artifacts limit the analytical sensitivity of SNV detection, especially at low variant allele frequencies (VAFs).To address the problem of relatively high noise levels in amplicon-based deep sequencing data (e.g. with the Ion AmpliSeq technology) in the context of SNV calling, we have developed a new bioinformatics tool called AmpliSolve. AmpliSolve uses a set of normal samples to model position-specific, strand-specific and nucleotide-specific background artifacts (noise), and deploys a Poisson model-based statistical framework for SNV detection.Our tests on both synthetic and real data indicate that AmpliSolve achieves a good trade-off between precision and sensitivity, even at VAF below 5% and as low as 1%. We further validate AmpliSolve by applying it to the detection of SNVs in 96 circulating tumor DNA samples at three clinically relevant genomic positions and compare the results to digital droplet PCR experiments.AmpliSolve is a new tool for in-silico estimation of background noise and for detection of low frequency SNVs in targeted deep sequencing data. Although AmpliSolve has been specifically designed for and tested on amplicon-based libraries sequenced with the Ion Torrent platform it can, in principle, be applied to other sequencing platforms as well. AmpliSolve is freely available at https://github.com/dkleftogi/AmpliSolve .
32.	Lauss, Martin, et al. (author) DNA methylation subgroups in melanoma are associated with proliferative and immunological processes. 2015 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 8:1 Journal article (peer-reviewed)abstract DNA methylation at CpG dinucleotides is modified in tumorigenesis with potential impact on transcriptional activity.
33.	Li, JJ, et al. (author) Effects of statin on circulating microRNAome and predicted function regulatory network in patients with unstable angina 2015 In: BMC medical genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 8, s. 12- Journal article (peer-reviewed)
34.	Lindholm Carlström, Eva, et al. (author) Linkage and exome analysis implicate multiple genes in non-syndromic intellectual disability in a large Swedish family 2019 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 12:1 Journal article (peer-reviewed)abstract BackgroundNon-syndromic intellectual disability is genetically heterogeneous with dominant, recessive and complex forms of inheritance. We have performed detailed genetic studies in a large multi-generational Swedish family, including several members diagnosed with non-syndromic intellectual disability. Linkage analysis was performed on 22 family members, nine affected with mild to moderate intellectual disability and 13 unaffected family members.Methods Family members were analyzed with Affymetrix Genome-Wide Human SNP Array 6.0 and the genetic data was used to detect copy number variation and to perform genome wide linkage analysis with the SNP High Throughput Linkage analysis system and the Merlin software. For the exome sequencing, the samples were prepared using the Sure Select Human All Exon Kit (Agilent Technologies, Santa Clara, CA, USA) and sequenced using the Ion Proton (TM) System. Validation of identified variants was performed with Sanger sequencing.ResultsThe linkage analysis results indicate that intellectual disability in this family is genetically heterogeneous, with suggestive linkage found on chromosomes 1q31-q41, 4q32-q35, 6p25 and 14q24-q31 (LOD scores of 2.4, simulated p-value of 0.000003 and a simulated genome-wide p-value of 0.06). Exome sequencing was then performed in 14 family members and 7 unrelated individuals from the same region. The analysis of coding variation revealed a pathogenic and candidate variants in different branches of the family. In three patients we find a known homozygous pathogenic mutation in the Homo sapiens solute carrier family 17 member 5 (SLC17A5), causing Salla disease. We also identify a deletion overlapping KDM3B and a duplication overlapping MAP3K4 and AGPAT4, both overlapping variants previously reported in developmental disorders.Conclusions DNA samples from the large family analyzed in this study were initially collected based on a hypothesis that affected members shared a major genetic risk factor. Our results show that a complex phenotype such as mild intellectual disability in large families from genetically isolated populations may show considerable genetic heterogeneity.
35.	Luyapan, Jennifer, et al. (author) A new efficient method to detect genetic interactions for lung cancer GWAS 2020 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 13:1 Journal article (peer-reviewed)abstract Background: Genome-wide association studies (GWAS) have proven successful in predicting genetic risk of disease using single-locus models; however, identifying single nucleotide polymorphism (SNP) interactions at the genome-wide scale is limited due to computational and statistical challenges. We addressed the computational burden encountered when detecting SNP interactions for survival analysis, such as age of disease-onset. To confront this problem, we developed a novel algorithm, called the Efficient Survival Multifactor Dimensionality Reduction (ES-MDR) method, which used Martingale Residuals as the outcome parameter to estimate survival outcomes, and implemented the Quantitative Multifactor Dimensionality Reduction method to identify significant interactions associated with age of disease-onset. Methods: To demonstrate efficacy, we evaluated this method on two simulation data sets to estimate the type I error rate and power. Simulations showed that ES-MDR identified interactions using less computational workload and allowed for adjustment of covariates. We applied ES-MDR on the OncoArray-TRICL Consortium data with 14,935 cases and 12,787 controls for lung cancer (SNPs = 108,254) to search over all two-way interactions to identify genetic interactions associated with lung cancer age-of-onset. We tested the best model in an independent data set from the OncoArray-TRICL data. Results: Our experiment on the OncoArray-TRICL data identified many one-way and two-way models with a single-base deletion in the noncoding region of BRCA1 (HR 1.24, P = 3.15 × 10–15), as the top marker to predict age of lung cancer onset. Conclusions: From the results of our extensive simulations and analysis of a large GWAS study, we demonstrated that our method is an efficient algorithm that identified genetic interactions to include in our models to predict survival outcomes.
36.	Meißner, Tobias, et al. (author) Profound impact of sample processing delay on gene expression of multiple myeloma plasma cells. 2015 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 8:1 Journal article (peer-reviewed)abstract Gene expression profiling (GEP) has significantly contributed to the elucidation of the molecular heterogeneity of multiple myeloma plasma cells (MMPC) and only recently it has been recommended for risk stratification. Prior to GEP MMPC need to be enriched resulting in an inability to immediately freeze bone marrow aspirates or use RNA stabilization reagents. As a result in multi-center MM trials sample processing delay due to shipping may be an important confounder of molecular analyses and risk stratification based on GEP data.
37.	Morin, Andreanne, et al. (author) Immunoseq : the identification of functionally relevant variants through targeted capture and sequencing of active regulatory regions in human immune cells 2016 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 9 Journal article (peer-reviewed)abstract Background: The observation that the genetic variants identified in genome-wide association studies (GWAS) frequently lie in non-coding regions of the genome that contain cis-regulatory elements suggests that altered gene expression underlies the development of many complex traits. In order to efficiently make a comprehensive assessment of the impact of non-coding genetic variation in immune related diseases we emulated the whole-exome sequencing paradigm and developed a custom capture panel for the known DNase I hypersensitive site (DHS) in immune cells - "Immunoseq". Results: We performed Immunoseq in 30 healthy individuals where we had existing transcriptome data from T cells. We identified a large number of novel non-coding variants in these samples. Relying on allele specific expression measurements, we also showed that our selected capture regions are enriched for functional variants that have an impact on differential allelic gene expression. The results from a replication set with 180 samples confirmed our observations. Conclusions: We show that Immunoseq is a powerful approach to detect novel rare variants in regulatory regions. We also demonstrate that these novel variants have a potential functional role in immune cells.
38.	Niroula, Abhishek, et al. (author) Harmful somatic amino acid substitutions affect key pathways in cancers. 2015 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 8:1 Journal article (peer-reviewed)abstract Cancer is characterized by the accumulation of large numbers of genetic variations and alterations of multiple biological phenomena. Cancer genomics has largely focused on the identification of such genetic alterations and the genes containing them, known as 'cancer genes'. However, the non-functional somatic variations out-number functional variations and remain as a major challenge. Recurrent somatic variations are thought to be cancer drivers but they are present in only a small fraction of patients.
39.	Osman, Abdimajid, et al. (author) Cross-ethnic analysis of common gene variants in hemostasis show lopsided representation of global populations in genetic databases 2022 In: BMC Medical Genomics. - : BMC. - 1755-8794. ; 15:1 Journal article (peer-reviewed)abstract A majority of studies reporting human genetic variants were performed in populations of European ancestry whereas other global populations, and particularly many ethnolinguistic groups in other continents, are heavily underrepresented in these studies. To investigate the extent of this disproportionate representation of global populations concerning variants of significance to thrombosis and hemostasis, 845 single nucleotide polymorphisms (SNPs) in and around 34 genes associated with thrombosis and hemostasis and included in the commercial Axiom Precision Medicine Research Array (PMRA) were evaluated, using gene frequencies in 3 African (Somali and Luhya in East Africa, and Yoruba in West Africa) and 14 non-African (admixed American, East Asian, European, South Asian, and sub-groups) populations. Among the populations studied, Europeans were observed to be the best represented population by the hemostatic SNPs included in the PMRA. The European population also presented the largest number of common pharmacogenetic and pathogenic hemostatic variants reported in the ClinVar database. The number of such variants decreased the farther the genetic distance a population was from Europeans, with Yoruba and East Asians presenting the least number of clinically significant hemostatic SNPs in ClinVar while also being the two genetically most distinct populations from Europeans among the populations compared. Current study shows the lopsided representation of global populations as regards to hemostatic genetic variants listed in different commercial SNP arrays, such as the PMRA, and reported in genetic databases while also underlining the importance of inclusion of non-European ethnolinguistic populations in genomics studies designed to discover variants of significance to bleeding and thrombotic disorders.
40.	Prasad, Rashmi B., et al. (author) Association of single nucleotide polymorphisms with insulin secretion, insulin sensitivity, and diabetes in women with a history of gestational diabetes mellitus 2021 In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 14:1 Journal article (peer-reviewed)abstract Background: This study investigated whether single nucleotide polymorphisms (SNPs) reported by previous genome-wide association studies (GWAS) to be associated with impaired insulin secretion, insulin resistance, and/or type 2 diabetes are associated with disposition index, the homeostasis model assessment of insulin resistance (HOMA-IR), and/or development of diabetes following a pregnancy complicated by gestational diabetes mellitus (GDM). Methods: Seventy-two SNPs were genotyped in 374 women with previous GDM from Southern Sweden. An oral glucose tolerance test was performed 1–2 years postpartum, although data on the diagnosis of diabetes were accessible up to 5 years postpartum. HOMA-IR and disposition index were used to measure insulin resistance and secretion, respectively. Results: The risk A-allele in the rs11708067 polymorphism of the adenylate cyclase 5 gene (ADCY5) was associated with decreased disposition index (beta = − 0.90, SE 0.38, p = 0.019). This polymorphism was an expression quantitative trait loci (eQTL) in islets for both ADCY5 and its antisense transcript. The risk C-allele in the rs2943641 polymorphism, near the insulin receptor substrate 1 gene (IRS1), showed a trend towards association with increased HOMA-IR (beta = 0.36, SE 0.18, p = 0.050), and the T-allele of the rs4607103 polymorphism, near the ADAM metallopeptidase with thrombospondin type 1 motif 9 gene (ADAMTS9), was associated with postpartum diabetes (OR = 2.12, SE 0.22, p = 0.00055). The genetic risk score (GRS) of the top four SNPs tested for association with the disposition index using equal weights was associated with the disposition index (beta = − 0.31, SE = 0.29, p = 0.00096). In addition, the GRS of the four SNPs studied for association with HOMA-IR using equal weights showed an association with HOMA-IR (beta = 1.13, SE = 0.48, p = 9.72874e−11). All analyses were adjusted for age, body mass index, and ethnicity. Conclusions: This study demonstrated the genetic susceptibility of women with a history of GDM to impaired insulin secretion and sensitivity and, ultimately, to diabetes development.
41.	Qiao, Y. M., et al. (author) An association study of IL2RA polymorphisms with cerebral palsy in a Chinese population 2022 In: Bmc Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 15:1 Journal article (peer-reviewed)abstract Background Cerebral palsy (CP), the most common physical disability of childhood, is a nonprogressive movement disorder syndrome. Eighty percent of cases are considered idiopathic without a clear cause. Evidence has shown that cytokine abnormalities are widely thought to contribute to CP. Methods An association between 6 SNPs (rs12244380, rs2025345, rs12722561, rs4749926, rs2104286 and rs706778) in IL2RA (interleukin 2 receptor subunit alpha) and CP was investigated using a case-control method based on 782 CP cases and 778 controls. The allele, genotype and haplotype frequencies of SNPs were assessed using the SHEsis program. Subgroup analyses based on complications and clinical subtypes were also conducted. Results Globally, no differences in genotype or allele frequencies for any SNPs remained significant after Bonferroni correction between patients and controls, except rs706778, which deviated from Hardy-Weinberg equilibrium and was excluded from further analyses. However, subgroup analysis revealed a significant association of rs2025345 with spastic tetraplegia (P genotype = 0.048 after correction) and rs12722561 with CP accompanied by global developmental delay (P allele = 0.045 after correction), even after Bonferroni correction. Conclusions These findings indicated that genetic variations in IL2RA are significantly associated with CP susceptibility in the Chinese Han population, suggesting that IL2RA is likely involved in the pathogenesis of CP. Further investigation with a larger sample size in a multiethnic population is needed to confirm the association.
42.	Vogelezang, Suzanne, et al. (author) Genetics of early-life head circumference and genetic correlations with neurological, psychiatric and cognitive outcomes. 2022 In: BMC medical genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 15:1 Journal article (peer-reviewed)abstract Head circumference is associated with intelligence and tracks from childhood into adulthood.We performed a genome-wide association study meta-analysis and follow-up of head circumference in a total of 29,192 participants between 6 and 30months of age.Seven loci reached genome-wide significance in the combined discovery and replication analysis of which three loci near ARFGEF2, MYCL1, and TOP1, were novel. We observed positive genetic correlations for early-life head circumference with adult intracranial volume, years of schooling, childhood and adult intelligence, but not with adult psychiatric, neurological, or personality-related phenotypes.The results of this study indicate that the biological processes underlying early-life head circumference overlap largely with those of adult head circumference. The associations of early-life head circumference with cognitive outcomes across the life course are partly explained by genetics.
43.	Yu, T., et al. (author) Association of NOS1 gene polymorphisms with cerebral palsy in a Han Chinese population: a case-control study 2018 In: Bmc Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 11:1 Journal article (peer-reviewed)abstract Background: Cerebral palsy (CP) is the leading cause of motor disability in children; however, its pathogenesis is unknown in most cases. Growing evidence suggests that Nitric oxide synthase 1 (NOS1) is involved in neural development and neurologic diseases. The purpose of this study was to determine whether genetic variants of NOS1 contribute to CP susceptibility in a Han Chinese population. Methods: A case-control study involving 652 CP patients and 636 healthy controls was conducted. Six SNPs in the NOS1 gene (rs3782219, rs6490121, rs2293054, rs10774909, rs3741475, and rs2682826) were selected, and the MassARRAY typing technique was applied for genotyping. Data analysis was conducted using SHEsis online software, and multiple test corrections were performed using SNPSpD online software. Results: There were no significant differences in genotype and allele frequencies between patients and controls for the SNPs except rs6490121, which deviated from Hardy-Weinberg equilibrium and was excluded from further analyses. Subgroup analysis revealed differences in genotype frequencies between the CP with neonatal encephalopathy group (CP + NE) and control group for rs10774909, rs3741475, and rs2682826 (after SNPSpD correction, p = 0.004, 0.012, and 0. 002, respectively). The T allele of NOS1 SNP rs3782219 was negatively associated with spastic quadriplegia (OR = 0.742, 95% CI = 0.600-0.918, after SNPSpD correction, p = 0.023). There were no differences in allele or genotype frequencies between CP subgroups and controls for the other genetic polymorphisms. Conclusions: NOS1 is associated with CP + NE and spastic quadriplegia, suggesting that NOS1 is likely involved in the pathogenesis of CP and that it is a potential therapeutic target for treatment of cerebral injury.
44.	Zlotina, A, et al. (author) A 300-kb microduplication of 7q36.3 in a patient with triphalangeal thumb-polysyndactyly syndrome combined with congenital heart disease and optic disc coloboma: a case report 2020 In: BMC medical genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 13:1, s. 175- Journal article (peer-reviewed)abstract BackgroundTriphalangeal thumb-polysyndactyly syndrome (TPT-PS) is a rare well-defined autosomal dominant disorder characterized by long thumbs with three phalanges combined with pre- and postaxial polydactyly/syndactyly of limbs. By now, the syndrome has been reported in several large families from different ethnic backgrounds, with a high degree of inter- and intrafamilial variability. The genome locus responsible for TPT-PS has been mapped to the 7q36.3 region harboring a long-range sonic hedgehog (SHH) regulatory sequence (ZRS). Both single-nucleotide variants and complete duplications of ZRS were shown to cause TPT-PS and similar limb phenotypes. TPT-PS usually forms as isolated limb pathology not associated with additional malformations, in particular, with cardiovascular abnormalities.Case presentationHere we report on a rare Russian neonatal case of TPT-PS combined with severe congenital heart disease, namely double outlet right ventricle, and microphthalmia with optic disc coloboma. Pedigree analysis revealed TPT-PS of various expressivity in 10 family members throughout five generations, while the cardiac defect and the eye pathology were detected only in the proband. To extend the knowledge on genotype–phenotype spectrum of TPT-PS, the careful clinical and genomic analysis of the family was performed. High-resolution array-based comparative genomic hybridization (array-CGH) revealed a ~ 300 kb microduplication of 7q36.3 locus (arr[GRCh37] 7q36.3(156385810_156684811) × 3) that co-segregated with TPT-PS in the proband and her mother. The duplication encompassed three genes includingLMBR1, the intron 5 of which is known to harbor ZRS. Based on whole-exome sequencing data, no additional pathogenic mutations or variants of uncertain clinical significance were found in morbid cardiac genes or genes associated with a microphthalmia/anophthalmia/coloboma spectrum of ocular malformations.ConclusionsThe results support the previous data, indicating that complete ZRS duplication underlies TPT-PS, and suggest a broader phenotypic impact of the 7q36.3 microduplication. Potential involvement of the 7q36.3 microduplication in the patient’s cardiac and eye malformations is discussed. However, the contribution of some additional genetic/epigenetic factors to the complex patient`s phenotype cannot be excluded entirely. Further comprehensive functional studies are needed to prove the possible involvement of the 7q36.3 locus in congenital heart disease and eye pathology.

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Author/Editor: Zhang, J. (2); Song, J. (2); Groop, Leif (2); Liedberg, Fredrik (2); Sonnhammer, Erik L L (2); Xia, L. (2); show more...; Jonasson, Jon (1); Carén, Helena, 1979 (1); Chen, H. (1); Cheng, Y. (1); Li, L. (1); Wang, T. (1); Zhang, F. (1); Xu, N. (1); Wang, Y. (1); Jönsson, Per (1); Betsholtz, C (1); Zhang, X. -L. (1); Lenner, Per (1); Johansson, Robert (1); Helleday, Thomas (1); Nielsen, Jens B, 196 ... (1); Lyssenko, Valeriya (1); Cavelier, Lucia (1); Landén, Mikael, 1966 (1); Jonsson, Lina, 1982 (1); Abel, Frida, 1974 (1); Kogner, Per (1); Nilsson, Staffan, 19 ... (1); Martinsson, Tommy, 1 ... (1); Jacobsson, Bo, 1960 (1); Bjorkegren, JLM (1); Edén, Patrik (1); Fioretos, Thoas (1); Eggermont, Alexander (1); Lind, Lars (1); Sjödahl, Gottfrid (1); Gudjonsson, Sigurdur (1); Adami, Hans Olov (1); Tandre, Karolina (1); Arner, Peter (1); Schiöth, Helgi B. (1); Fellman, Vineta (1); Lundeberg, Joakim (1); Andersson, Anna (1); Kere, Juha (1); Melander, Olle (1); Johansson, Jan-Erik (1); Axelsson, Tomas (1); Lundin, Samuel B, 19 ... (1); show less...

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