EU financed projects

The European infrastructure for translational medicine (EATRIS) flagship project, EATRIS-Plus, aims to build capabilities and deliver innovative scientific tools to support the long-term sustainability of European research infrastructures for Personalised Medicine. The main goal of EATRIS-Plus is to develop capacities in the field of Personalised Medicine (particularly -omics technologies) to better serve academia and industry.

Publications:

• Xiao W, Ren L, Chen Z, Fang LT … Nordlund J, Liljedahl U … Wang C, Shi L (2021) Toward best practice in cancer mutation detection with whole-genome and whole-exome sequencing. Nat Biotechnol 39 (https://doi.org/10.1038/s41587-021-00994-5 )
• Fang LT, Zhu B, Zhao Y, Chen W, … Nordlund J, Liljedahl U … Wang C, Xiao W (2021) Establishing community reference samples, data and call sets for benchmarking cancer mutation detection using whole-genome sequencing Nat Biotechnol 39 (https://doi.org/10.1038/s41587-021-00993-6)
• Zhao Y, Fang LT, Shen TW, Choudhari S … Nordlund J, Liljedahl U, Foox J, Mason C, Xiao W (2021) Whole genome and exome sequencing reference datasets from a multi-center and cross-platform benchmark study Scientific Data, in press. (https://doi.org/10.1101/2021.02.27.433136 )

Prediction-ADR aims to discover the genetic factors predisposing patients to adverse drug reactions (ADRs) from cardiovascular disease (CVD) drugs. This will be achieved by assembling a consented blood bank and DNA for a population of ~500 cases of ACEi induced angioedema and statin induced myopathy defined using a standardised phenotypic criteria. An innovative next generation sequencing strategy will be used to find predisposing genetic changes to myopathy and angioedema.

The Molecular Medicine group is part of the BLUEPRINT project as an associated member. The BLUEPRINT consortium has the aim to increase the understanding of how genes are activated or repressed in both healthy and diseased human cells. BLUEPRINT will focus on distinct types of haematopoietic cells from healthy individuals and on their malignant leukaemic counterparts. The goal is to generate at least 100 reference epigenomes and study them to advance and exploit knowledge of the underlying biological processes and mechanisms in health and disease.

European Genotyping and Sequencing Infrastructure (ESGI). ESGI is a distributed infrastructure for providing transnational access to high through-put sequencing and human genotyping to European researchers, and for technology development in this area. The major sequencing and genotyping centers in Europe, like the Wellcome Trust Sanger Institute and the French Genotyping Center (CNG) and the European Bioinformatics Institute (EBI) are partners in the ESGI. As partner in ESGI the task of the Molecular Medicine group is to develop laboratory protocols and bioinformatic tools for analysis of allele-specific gene expression. The SNP&SEQ technology platform in Uppsala provides transnational access to genotyping and second generation sequencing services to European researchers.

Publications:

• Lopes F. et al. (2016) Identification of novel genetic causes of Rett syndrome-like phenotypes. J Med Genet 53(3), 190-199
• Madrigal I. et al. (2016) A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability. Eur J Hum Genet 24(8), 1117-1123
• Limbach M. et al. (2016) Epigenetic profiling in CD4+ and CD8+ T cells from Graves' disease patients reveals changes in genes associated with T cell receptor signaling. J Autoimmun 67, 46-56
• Madrigal I. et al. (2014) Efficient application of next-generation sequencing for the diagnosis of rare genetic syndromes. J Clin Pathol 67(12), 1099-1103 

As partners of the Geuvadis consortium the Molecular Medicine group and the SNP&SEQ technology platform work together with 11 major sequencing and genotyping centers across Europe to define best laboratory, data analysis, data sharing and ethics practices for next generation transcriptome and exome sequencing.

Publications:

• Ferreira P.G. et al. (2016) Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing. Sci Rep6:32406
• Rivas M.A. et al. (2015) Effect of predicted protein-truncating genetic variants on the human transcriptome. Science 348(6235), 666-669
• Greger L. et al. (2014) Tandem RNA Chimeras Contribute to Transcriptome Diversity in Human Population and Are Associated with Intronic Genetic Variants. PLoS One 9(8), e104567
• Lappalainen T. et al. (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature, 501(7468), 506-511
• t Hoen P.A.C. et al. (2013) Reproducibility of high-throughput mRNA and small RNA sequencing across laboratories. Nat Biotech, 31(11), 1015-1022

The Molecular Medicine group participates in the Engage project by establishing methodology for methyl capture and by genome-wide analysis of DNA methylation by second generation sequencing of samples from European twin cohorts. We also contribute to Engage by SNP genotyping on various scales using the resources of the SNP&SEQ technology platform.

Publications:

• Ehret GB, et al (2016) The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet 48(10), 1171-1184
• den Hoed M et al (2015) GWAS-identified loci for coronary heart disease are associated with intima-media thickness and plaque presence at the carotid artery bulb. Atherosclerosis239(2), 304-310
• Bahl A et al (2015) Hormone Replacement Therapy Associated White Blood Cell DNA Methylation and Gene Expression are Associated With Within-Pair Differences of Body Adiposity and Bone Mass. Twin Res Hum Genet 18(06), 647-661
• Hägg S et al (2015) Adiposity as a cause of cardiovascular disease: a Mendelian randomization study. Int J Epidemiol 44(2), 578-586
• Prokopenko I et al (2014) A Central Role for GRB10 in Regulation of Islet Function in Man. PLoS Genet10(4), e1004235
• Fall et al. (2013) The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis. PLoS Med 10(6), e1001474
• Surakka et al (2012) A Genome-Wide Association Study of Monozygotic Twin-Pairs Suggests a Locus Related to Variability of Serum High-Density Lipoprotein Cholesterol. Twin Res Hum Genet15(6), 691-699
• Dastani et al. (2012) Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals. PLoS Genet 8(3), e1002607
• Palmer et al. (2012) A Genome-Wide Association Search for Type 2 Diabetes Genes in African Americans. PLoS One 7(1), e29202
• Chambers et al. (2011) Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet. 43(11):1131-1138
• Kiialainen et al. (2011) Performance of microarray and liquid based capture methods for target enrichment for massively parallel sequencing and SNP discovery. PloS One, 6(2):e16486
• Speliotes et al. (2010) Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nature Genetics 42, 937–948
• Dupuis et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Gen, 42:105-116
• Heid et al. (2010) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Gen, 42:949-60
• Milani et al. (2009) DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia. Blood, 115:1214-1225
• Saxena et al. (2010) Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Gen, 42:142-148
• Newton-Cheh et al. (2009) Genome-wide association study identifies eight loci associated with blood pressure. Nat Gen, 41:666-667

The aim of the Cardiogenics project is to identify genetic roots of coronary artery disease by combining genome wide association studies with transcriptomic and functional genomic investigation of risk gene variants. The task of the Molecular Medicine group as partner in Cardiogenics is to study gene cis-regulation of gene expression using allele-specific gene expression analysis in monocytes from healthy blood donors.

Publications:

• Nelson CP, et al (2015) Genetically Determined Height and Coronary Artery Disease. N Engl J Med 372(17), 1608-1618
• den Hoed M et al (2015) GWAS-identified loci for coronary heart disease are associated with intima-media thickness and plaque presence at the carotid artery bulb. Atherosclerosis 239(2), 304-310
• Carlsson Almlöf et al (2014) Single Nucleotide Polymorphisms with Cis-Regulatory Effects on Long Non-Coding Transcripts in Human Primary Monocytes. PLoS One 9(7), e102612
• Deloukas et al. (2013) Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 45(1), 25-33
• Almlöf et al. (2012) Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression. PLoS One 7(12), e52260
• Greliche et al. (2012) Comprehensive exploration of the effects of miRNA SNPs on monocyte gene expression. PLoS One 7(9), e45863
• The Coronary Artery Disease (C4D) Genetics Consortium (2011) A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet, 43:339-344
• Heinig M et al. (2010) A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467(7314), 460-464
• Speliotes et al. (2010) Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nature Genetics 42, 937–948
• Schunkert et al. (2008) Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease. Circulation, 117:1675-84