Browsing by Subject "TRANSCRIPTOME"

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  • Rahikkala, Elisa; Urpa, Lea; Ghimire, Bishwa; Topa, Hande; Kurki, Mitja; Koskela, Maryna; Airavaara, Mikko; Hämäläinen, Eija; Pylkäs, Katri; Körkkö, Jarmo; Savolainen, Helena; Suoranta, Anu; Bertoli-Avella, Aida; Rolfs, Arndt; Mattila, Pirkko; Daly, Mark; Palotie, Aarno; Pietiläinen, Olli; Moilanen, Jukka; Kuismin, Outi (2022)
    Biallelic loss-of-function variants in the SMG9 gene, encoding a regulatory subunit of the mRNA nonsense-mediated decay (NMD) machinery, are reported to cause heart and brain malformation syndrome. Here we report five patients from three unrelated families with intellectual disability (ID) and a novel pathogenic SMG9 c.551 T > C p.(Val184Ala) homozygous missense variant, identified using exome sequencing. Sanger sequencing confirmed recessive segregation in each family. SMG9 c.551T > C p.(Val184Ala) is most likely an autozygous variant identical by descent. Characteristic clinical findings in patients were mild to moderate ID, intention tremor, pyramidal signs, dyspraxia, and ocular manifestations. We used RNA sequencing of patients and age- and sex-matched healthy controls to assess the effect of the variant. RNA sequencing revealed that the SMG9 c.551T > C variant did not affect the splicing or expression level of SMG9 gene products, and allele-specific expression analysis did not provide evidence that the nonsense mRNA-induced NMD was affected. Differential gene expression analysis identified prevalent upregulation of genes in patients, including the genes SMOX, OSBP2, GPX3, and ZNF155. These findings suggest that normal SMG9 function may be involved in transcriptional regulation without affecting nonsense mRNA-induced NMD. In conclusion, we demonstrate that the SMG9 c.551T > C missense variant causes a neurodevelopmental disorder and impacts gene expression. NMD components have roles beyond aberrant mRNA degradation that are crucial for neurocognitive development.
  • PanScan PanC4 consortia; Walsh, Naomi; Zhang, Han; Männistö, Satu; Weiderpass, Elisabete (2019)
    Background Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P Conclusion Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
  • Nikparvar, Bahareh; Andreevskaya, Margarita; Duru, Ilhan C.; Bucur, Florentina I.; Grigore-Gurgu, Leontina; Borda, Daniela; Nicolau, Anca I.; Riedel, Christian U.; Auvinen, Petri; Bar, Nadav (2021)
    Background The pathogen Listeria (L.) monocytogenes is known to survive heat, cold, high pressure, and other extreme conditions. Although the response of this pathogen to pH, osmotic, temperature, and oxidative stress has been studied extensively, its reaction to the stress produced by high pressure processing HPP (which is a preservation method in the food industry), and the activated gene regulatory network (GRN) in response to this stress is still largely unknown. Results We used RNA sequencing transcriptome data of L. monocytogenes (ScottA) treated at 400 MPa and 8(circle)C, for 8 min and combined it with current information in the literature to create a transcriptional regulation database, depicting the relationship between transcription factors (TFs) and their target genes (TGs) in L. monocytogenes. We then applied network component analysis (NCA), a matrix decomposition method, to reconstruct the activities of the TFs over time. According to our findings, L. monocytogenes responded to the stress applied during HPP by three statistically different gene regulation modes: survival mode during the first 10 min post-treatment, repair mode during 1 h post-treatment, and re-growth mode beyond 6 h after HPP. We identified the TFs and their TGs that were responsible for each of the modes. We developed a plausible model that could explain the regulatory mechanism that L. monocytogenes activated through the well-studied CIRCE operon via the regulator HrcA during the survival mode. Conclusions Our findings suggest that the timely activation of TFs associated with an immediate stress response, followed by the expression of genes for repair purposes, and then re-growth and metabolism, could be a strategy of L. monocytogenes to survive and recover extreme HPP conditions. We believe that our results give a better understanding of L. monocytogenes behavior after exposure to high pressure that may lead to the design of a specific knock-out process to target the genes or mechanisms. The results can help the food industry select appropriate HPP conditions to prevent L. monocytogenes recovery during food storage.
  • Zhang, Sidi; Samocha, Kaitlin E.; Rivas, Manuel A.; Karczewski, Konrad J.; Daly, Emma; Schmandt, Ben; Neale, Benjamin M.; MacArthur, Daniel G.; Daly, Mark J. (2018)
    Variation in RNA splicing (i.e., alternative splicing) plays an important role in many diseases. Variants near 5' and 3' splice sites often affect splicing, but the effects of these variants on splicing and disease have not been fully characterized beyond the two "essential" splice nucleotides flanking each exon. Here we provide quantitative measurements of tolerance to mutational disruptions by position and reference allele-alternative allele combinations. We show that certain reference alleles are particularly sensitive to mutations, regardless of the alternative alleles into which they are mutated. Using public RNA-seq data, we demonstrate that individuals carrying such variants have significantly lower levels of the correctly spliced transcript, compared to individuals without them, and confirm that these specific substitutions are highly enriched for known Mendelian mutations. Our results propose a more refined definition of the "splice region" and offer a new way to prioritize and provide functional interpretation of variants identified in diagnostic sequencing and association studies.
  • Wisgrill, Lukas; Fyhrquist, Nanna; Ndika, Joseph; Paalanen, Laura; Berger, Angelika; Laatikainen, Tiina; Karisola, Piia; Haahtela, Tari; Alenius, Harri (2022)
    Background In allergic patients, clinical symptoms caused by pollen remind of symptoms triggered by viral respiratory infections, which are also the main cause of asthmatic exacerbations. In patients sensitized to birch pollen, Bet v 1 is the major symptom-causing allergen. Immune mechanisms driving Bet v 1-related responses of human blood cells have not been fully characterized. Objective To characterize the immune response to Bet v 1 in peripheral blood in patients allergic to birch pollen. Methods The peripheral blood mononuclear cells of birch-allergic (n = 24) and non-allergic (n = 47) adolescents were stimulated ex-vivo followed by transcriptomic profiling. Systems-biology approaches were employed to decipher disease-relevant gene networks and deconvolution of associated cell populations. Results Solely in birch-allergic patients, co-expression analysis revealed activation of networks of innate immunity and antiviral signalling as the immediate response to Bet v 1 stimulation. Toll-like receptors and signal transducer transcription were the main drivers of gene expression patterns. Macrophages and dendritic cells were the main cell subsets responding to Bet v 1. Conclusions and clinical relevance In birch-pollen-allergic patients, the activated innate immune networks seem to be, in part, the same as those activated during viral infections. This tendency of the immune system to read pollens as viruses may provide new insight to allergy prevention and treatment.
  • Madissoon, Elo; Jouhilahti, Eeva-Mari; Vesterlund, Liselotte; Tohonen, Virpi; Krjutskov, Kaarel; Petropoulos, Sophie; Einarsdottir, Elisabet; Linnarssons, Sten; Lanner, Fredrik; Mansson, Robert; Hovatta, Outi; Burglin, Thomas R.; Katayama, Shintaro; Kere, Juha (2016)
    PAIRED (PRD)-like homeobox genes belong to a class of predicted transcription factor genes. Several of these PRD-like homeobox genes have been predicted in silico from genomic sequence but until recently had no evidence of transcript expression. We found recently that nine PRD-like homeobox genes, ARGFX, CPHX1, CPHX2, DPRX, DUXA, DUXB, NOBOX, TPRX1 and TPRX2, were expressed in human preimplantation embryos. In the current study we characterized these PRD-like homeobox genes in depth and studied their functions as transcription factors. We cloned multiple transcript variants from human embryos and showed that the expression of these genes is specific to embryos and pluripotent stem cells. Overexpression of the genes in human embryonic stem cells confirmed their roles as transcription factors as either activators (CPHX1, CPHX2, ARGFX) or repressors (DPRX, DUXA, TPRX2) with distinct targets that could be explained by the amino acid sequence in homeodomain. Some PRD-like homeodomain transcription factors had high concordance of target genes and showed enrichment for both developmentally important gene sets and a 36 bp DNA recognition motif implicated in Embryo Genome Activation (EGA). Our data implicate a role for these previously uncharacterized PRD-like homeodomain proteins in the regulation of human embryo genome activation and preimplantation embryo development.
  • Byers, Kelsey J. R. P.; Darragh, Kathy; Fernanda Garza, Sylvia; Abondano Almeida, Diana; Warren, Ian A.; Rastas, Pasi M. A.; Merrill, Richard M.; Schulz, Stefan; McMillan, W. Owen; Jiggins, Chris D. (2021)
    The degree to which loci promoting reproductive isolation cluster in the genome-that is, the genetic architecture of reproductive isolation-can influence the tempo and mode of speciation. Tight linkage between these loci can facilitate speciation in the face of gene flow. Pheromones play a role in reproductive isolation in many Lepidoptera species, and the role of endogenously produced compounds as secondary metabolites decreases the likelihood of pleiotropy associated with many barrier loci. Heliconius butterflies use male sex pheromones to both court females (aphrodisiac wing pheromones) and ward off male courtship (male-transferred antiaphrodisiac genital pheromones), and it is likely that these compounds play a role in reproductive isolation between Heliconius species. Using a set of backcross hybrids between H. melpomene and H. cydno, we investigated the genetic architecture of putative male pheromone compound production. We found a set of 40 significant quantitative trait loci (QTL) representing 33 potential pheromone compounds. QTL clustered significantly on two chromosomes, chromosome 8 for genital compounds and chromosome 20 for wing compounds, and chromosome 20 was enriched for potential pheromone biosynthesis genes. There was minimal overlap between pheromone QTL and known QTL for mate choice and color pattern. Nonetheless, we did detect linkage between a QTL for wing androconial area and optix, a color pattern locus known to play a role in reproductive isolation in these species. This tight clustering of putative pheromone loci might contribute to coincident reproductive isolating barriers, facilitating speciation despite ongoing gene flow.
  • Kautt, Andreas F.; Kratochwil, Claudius F.; Nater, Alexander; Machado-Schiaffino, Gonzalo; Olave, Melisa; Henning, Frederico; Torres-Dowdall, Julian; Härer, Andreas; Hulsey, C. Darrin; Franchini, Paolo; Pippel, Martin; Myers, Eugene W.; Meyer, Axel (2020)
    Population genomic analyses of Midas cichlid fishes in young Nicaraguan crater lakes suggest that sympatric speciation is promoted by polygenic architectures. The transition from 'well-marked varieties' of a single species into 'well-defined species'-especially in the absence of geographic barriers to gene flow (sympatric speciation)-has puzzled evolutionary biologists ever since Darwin(1,2). Gene flow counteracts the buildup of genome-wide differentiation, which is a hallmark of speciation and increases the likelihood of the evolution of irreversible reproductive barriers (incompatibilities) that complete the speciation process(3). Theory predicts that the genetic architecture of divergently selected traits can influence whether sympatric speciation occurs(4), but empirical tests of this theory are scant because comprehensive data are difficult to collect and synthesize across species, owing to their unique biologies and evolutionary histories(5). Here, within a young species complex of neotropical cichlid fishes (Amphilophus spp.), we analysed genomic divergence among populations and species. By generating a new genome assembly and re-sequencing 453 genomes, we uncovered the genetic architecture of traits that have been suggested to be important for divergence. Species that differ in monogenic or oligogenic traits that affect ecological performance and/or mate choice show remarkably localized genomic differentiation. By contrast, differentiation among species that have diverged in polygenic traits is genomically widespread and much higher overall, consistent with the evolution of effective and stable genome-wide barriers to gene flow. Thus, we conclude that simple trait architectures are not always as conducive to speciation with gene flow as previously suggested, whereas polygenic architectures can promote rapid and stable speciation in sympatry.
  • Berta, Davide G.; Kuisma, Heli; Välimäki, Niko; Räisänen, Maritta; Jäntti, Maija; Pasanen, Annukka; Karhu, Auli; Kaukomaa, Jaana; Taira, Aurora; Cajuso, Tatiana; Nieminen, Sanna; Penttinen, Rosa-Maria; Ahonen, Saija; Lehtonen, Rainer; Mehine, Miika; Vahteristo, Pia; Jalkanen, Jyrki; Sahu, Biswajyoti; Ravantti, Janne; Mäkinen, Netta; Rajamäki, Kristiina; Palin, Kimmo; Taipale, Jussi; Heikinheimo, Oskari; Bützow, Ralf; Kaasinen, Eevi; Aaltonen, Lauri A. (2021)
    One in four women suffers from uterine leiomyomas (ULs)-benign tumours of the uterine wall, also known as uterine fibroids-at some point in premenopausal life. ULs can cause excessive bleeding, pain and infertility(1), and are a common cause of hysterectomy(2). They emerge through at least three distinct genetic drivers: mutations in MED12 or FH, or genomic rearrangement of HMGA2(3). Here we created genome-wide datasets, using DNA, RNA, assay for transposase-accessible chromatin (ATAC), chromatin immunoprecipitation (ChIP) and HiC chromatin immunoprecipitation (HiChIP) sequencing of primary tissues to profoundly understand the genesis of UL. We identified somatic mutations in genes encoding six members of the SRCAP histone-loading complex(4), and found that germline mutations in the SRCAP members YEATS4 and ZNHIT1 predispose women to UL. Tumours bearing these mutations showed defective deposition of the histone variant H2A.Z. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in tumours bearing SRCAP complex mutations. In these tumours, open chromatin emerged at transcription start sites where H2A.Z was lost, which was associated with upregulation of genes. Furthermore, YEATS4 defects were associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice(5). Our work describes a potential mechanism of tumorigenesis-epigenetic instability caused by deficient H2A.Z deposition-and suggests that ULs arise through an aberrant differentiation program driven by deranged chromatin, emanating from a small number of mutually exclusive driver mutations.
  • Dias, Fernando H.C.; Williams, Lucia; Mumey, Brendan; Tomescu, Alexandru I. (2022)
    Minimum flow decomposition (MFD) is an NP-hard problem asking to decompose a network flow into a minimum set of paths (together with associated weights). Variants of it are powerful models in multiassembly problems in Bioinformatics, such as RNA assembly. Owing to its hardness, practical multiassembly tools either use heuristics or solve simpler, polynomial time-solvable versions of the problem, which may yield solutions that are not minimal or do not perfectly decompose the flow. Here, we provide the first fast and exact solver for MFD on acyclic flow networks, based on Integer Linear Programming (ILP). Key to our approach is an encoding of all the exponentially many solution paths using only a quadratic number of variables. We also extend our ILP formulation to many practical variants, such as incorporating longer or paired-end reads, or minimizing flow errors. On both simulated and real-flow splicing graphs, our approach solves any instance in
  • Alonso Serra, Juan Antonio; Shi, Xueping; Peaucelle, Alexis; Rastas, Pasi; Bourdon, Matthieu; Immanen, Juha; Takahashi, Junko; Koivula, Hanna; Eswaran, Gugan; Muranen, Sampo Johannes; Help-Rinta-Rahko, Hanna; Smolander, Olli-Pekka; Su, Chang; Safronov, Omid; Gerber, Lorenz; Salojärvi, Jarkko; Hagqvist, Risto; Mähönen, Ari Pekka; Helariutta, Yrjö; Nieminen, Kaisa (2020)
    Tree architecture has evolved to support a top-heavy above-ground biomass, but this integral feature poses a weight-induced challenge to trunk stability. Maintaining an upright stem is expected to require vertical proprioception through feedback between sensing stem weight and responding with radial growth. Despite its apparent importance, the principle by which plant stems respond to vertical loading forces remains largely unknown. Here, by manipulating the stem weight of downy birch (Betula pubescens) trees, we show that cambial development is modulated systemically along the stem. We carried out a genetic study on the underlying regulation by combining an accelerated birch flowering program with a recessive mutation at the ELIMAKI locus (EKI), which causes a mechanically defective response to weight stimulus resulting in stem collapse after just 3 months. We observed delayed wood morphogenesis in eki compared with WT, along with a more mechanically elastic cambial zone and radial compression of xylem cell size, indicating that rapid tissue differentiation is critical for cambial growth under mechanical stress. Furthermore, the touch-induced mechanosensory pathway was transcriptionally misregulated in eki, indicating that the ELIMAKI locus is required to integrate the weight-growth feedback regulation. By studying this birch mutant, we were able to dissect vertical proprioception from the gravitropic response associated with reaction wood formation. Our study provides evidence for both local and systemic responses to mechanical stimuli during secondary plant development.
  • Sablok, Gaurav; Powell, Jonathan J.; Kazan, Kemal (2017)
    Plants use a wide range of mechanisms to adapt to different environmental stresses. One of the earliest responses displayed under stress is rapid alterations in stress responsive gene expression that has been extensively analyzed through expression profiling such as microarrays and RNA-sequencing. Recently, expression profiling has been complemented with proteome analyses to establish a link between transcriptional and the corresponding translational changes. However, proteome profiling approaches have their own technical limitations. More recently, ribosome-associated mRNA profiling has emerged as an alternative and a robust way of identifying translating mRNAs, which are a set of mRNAs associated with ribosomes and more likely to contribute to proteome abundance. In this article, we briefly review recent studies that examined the processes affecting the abundance of translating mRNAs, their regulation during plant development and tolerance to stress conditions and plant factors affecting the selection of translating mRNA pools. This review also highlights recent findings revealing differential roles of alternatively spliced mRNAs and their translational control during stress adaptation. Overall, better understanding of processes involved in the regulation of translating mRNAs has obvious implications for improvement of stress tolerance in plants.
  • Kuosmanen, Anna; Norri, Tuukka; Mäkinen, Veli (2018)
    Transcript prediction can be modeled as a graph problem where exons are modeled as nodes and reads spanning two or more exons are modeled as exon chains. Pacific Biosciences third-generation sequencing technology produces significantly longer reads than earlier second-generation sequencing technologies, which gives valuable information about longer exon chains in a graph. However, with the high error rates of third-generation sequencing, aligning long reads correctly around the splice sites is a challenging task. Incorrect alignments lead to spurious nodes and arcs in the graph, which in turn lead to incorrect transcript predictions. We survey several approaches to find the exon chains corresponding to long reads in a splicing graph, and experimentally study the performance of these methods using simulated data to allow for sensitivity/precision analysis. Our experiments show that short reads from second-generation sequencing can be used to significantly improve exon chain correctness either by error-correcting the long reads before splicing graph creation, or by using them to create a splicing graph on which the long-read alignments are then projected. We also study the memory and time consumption of various modules, and show that accurate exon chains lead to significantly increased transcript prediction accuracy. Availability: The simulated data and in-house scripts used for this article are available at http://www.cs.helsinki.fi/group/gsa/exon-chains/exon-chains-bib.tar.bz2.
  • Eising, Else; Huisman, Sjoerd M. H.; Mahfouz, Ahmed; Vijfhuizen, Lisanne S.; Anttila, Verneri; Winsvold, Bendik S.; Kurth, Tobias; Ikram, M. Arfan; Freilinger, Tobias; Kaprio, Jaakko; Boomsma, Dorret I.; van Duijn, Cornelia M.; Jarvelin, Marjo-Riitta R.; Zwart, John-Anker; Quaye, Lydia; Strachan, David P.; Kubisch, Christian; Dichgans, Martin; Smith, George Davey; Stefansson, Kari; Palotie, Aarno; Chasman, Daniel I.; Ferrari, Michel D.; Terwindt, Gisela M.; de Vries, Boukje; Nyholt, Dale R.; Lelieveldt, Boudewijn P. F.; van den Maagdenberg, Arn M. J. M.; Reinders, Marcel J. T. (2016)
    Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.
  • Katayama, Shintaro; Skoog, Tiina; Jouhilahti, Eeva-Mari; Siitonen, H. Annika; Nuutila, Kristo; Tervaniemi, Mari H.; Vuola, Jyrki; Johnsson, Anna; Lonnerberg, Peter; Linnarsson, Sten; Elomaa, Outi; Kankuri, Esko; Kere, Juha (2015)
    Background: Keratinocytes (KCs) are the most frequent cells in the epidermis, and they are often isolated and cultured in vitro to study the molecular biology of the skin. Cultured primary cells and various immortalized cells have been frequently used as skin models but their comparability to intact skin has been questioned. Moreover, when analyzing KC transcriptomes, fluctuation of polyA+ RNA content during the KCs' lifecycle has been omitted. Results: We performed STRT RNA sequencing on 10 ng samples of total RNA from three different sample types: i) epidermal tissue (split-thickness skin grafts), ii) cultured primary KCs, and iii) HaCaT cell line. We observed significant variation in cellular polyA+ RNA content between tissue and cell culture samples of KCs. The use of synthetic RNAs and SAMstrt in normalization enabled comparison of gene expression levels in the highly heterogenous samples and facilitated discovery of differences between the tissue samples and cultured cells. The transcriptome analysis sensitively revealed genes involved in KC differentiation in skin grafts and cell cycle regulation related genes in cultured KCs and emphasized the fluctuation of transcription factors and non-coding RNAs associated to sample types. Conclusions: The epidermal keratinocytes derived from tissue and cell culture samples showed highly different polyA+ RNA contents. The use of SAMstrt and synthetic RNA based normalization allowed the comparison between tissue and cell culture samples and thus proved to be valuable tools for RNA-seq analysis with translational approach. Transciptomics revealed clear difference both between tissue and cell culture samples and between primary KCs and immortalized HaCaT cells.
  • Int Headache Genetics Consortium; HUNT All-in Headache; Danish Blood Donor Study Genomic C (2022)
    Genome-wide association analyses identify 123 susceptibility loci for migraine and implicate neurovascular mechanisms in its pathophysiology. Subtype analyses highlight risk loci specific for migraine with or without aura in addition to shared risk variants. Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.
  • Psychiat Genomics Consortium; 23andMe Res Team; Psychosis Endopheno-types Int Cons; Wellcome Trust Case Control Consor; Lee, Phil H.; Anttila, Verneri; Won, Hyejung; Kaprio, Jaakko; Keski-Rahkonen, Anna; Churchhouse, Claire; Rehnström, Karola; Raevuori, Anu; Palotie, Aarno; Daly, Mark J.; Neale, Benjamin M. (2019)
    Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.
  • Sood, Sanjana; Szkop, Krzysztof J.; Nakhuda, Asif; Gallagher, Iain J.; Murie, Carl; Brogan, Robert J.; Kaprio, Jaakko; Kainulainen, Heikki; Atherton, Philip J.; Kujala, Urho M.; Gustafsson, Thomas; Larsson, Ola; Timmons, James A. (2016)
    DNA microarrays and RNAseq are complementary methods for studying RNA molecules. Current computational methods to determine alternative exon usage (AEU) using such data require impractical visual inspection and still yield high false-positive rates. Integrated Gene and Exon Model of Splicing (iGEMS) adapts a gene-level residuals model with a gene size adjusted false discovery rate and exon-level analysis to circumvent these limitations. iGEMS was applied to two new DNA microarray datasets, including the high coverage Human Transcriptome Arrays 2.0 and performance was validated using RT-qPCR. First, AEU was studied in adipocytes treated with (n = 9) or without (n = 8) the anti-diabetes drug, rosiglitazone. iGEMS identified 555 genes with AEU, and robust verification by RT-qPCR (similar to 90%). Second, in a three-way human tissue comparison (muscle, adipose and blood, n = 41) iGEMS identified 4421 genes with at least one AEU event, with excellent RT-qPCR verification (95%, n = 22). Importantly, iGEMS identified a variety of AEU events, including 3'UTR extension, as well as exon inclusion/exclusion impacting on protein kinase and extracellular matrix domains. In conclusion, iGEMS is a robust method for identification of AEU while the variety of exon usage between human tissues is 5-10 times more prevalent than reported by the Genotype-Tissue Expression consortium using RNA sequencing.
  • Eising, Else; de Leeuw, Christiaan; Min, Josine L.; Anttila, Verneri; Verheijen, Mark H. G.; Terwindt, Gisela M.; Dichgans, Martin; Freilinger, Tobias; Kubisch, Christian; Ferrari, Michel D.; Smit, August B.; de Vries, Boukje; Palotie, Aarno; van den Maagdenberg, Arn M. J. M.; Posthuma, Danielle; Int Headache Genetics Consortium (2016)
    Background Migraine is a common episodic brain disorder characterized by recurrent attacks of severe unilateral headache and additional neurological symptoms. Two main migraine types can be distinguished based on the presence of aura symptoms that can accompany the headache: migraine with aura and migraine without aura. Multiple genetic and environmental factors confer disease susceptibility. Recent genome-wide association studies (GWAS) indicate that migraine susceptibility genes are involved in various pathways, including neurotransmission, which have already been implicated in genetic studies of monogenic familial hemiplegic migraine, a subtype of migraine with aura. Methods To further explore the genetic background of migraine, we performed a gene set analysis of migraine GWAS data of 4954 clinic-based patients with migraine, as well as 13,390 controls. Curated sets of synaptic genes and sets of genes predominantly expressed in three glial cell types (astrocytes, microglia and oligodendrocytes) were investigated. Discussion Our results show that gene sets containing astrocyte- and oligodendrocyte-related genes are associated with migraine, which is especially true for gene sets involved in protein modification and signal transduction. Observed differences between migraine with aura and migraine without aura indicate that both migraine types, at least in part, seem to have a different genetic background.
  • Hakonen, Elina; Chandra, Vikash; Fogarty, Christopher L.; Yu, Nancy Yiu-Lin; Ustinov, Jarkko; Katayama, Shintaro; Galli, Emilia; Danilova, Tatiana; Lindholm, Paivi; Vartiainen, Aki; Einarsdottir, Elisabet; Krjutskov, Kaarel; Kere, Juha; Saarma, Mart; Lindahl, Maria; Otonkoski, Timo (2018)
    There is a great need to identify factors that could protect pancreatic beta cells against apoptosis or stimulate their replication and thus prevent or reverse the development of diabetes. One potential candidate is mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum (ER) stress inducible protein. Manf knockout mice used as a model of diabetes develop the condition because of increased apoptosis and reduced proliferation of beta cells, apparently related to ER stress. Given this novel association between MANF and beta cell death, we studied the potential of MANF to protect human beta cells against experimentally induced ER stress. Primary human islets were challenged with proinflammatory cytokines, with or without MANF. Cell viability was analysed and global transcriptomic analysis performed. Results were further validated using the human beta cell line EndoC-beta H1. There was increased expression and secretion of MANF in human beta cells in response to cytokines. Addition of recombinant human MANF reduced cytokine-induced cell death by 38% in human islets (p <0.05). MANF knockdown in EndoC-beta H1 cells led to increased ER stress after cytokine challenge. Mechanistic studies showed that the protective effect of MANF was associated with repression of the NF-kappa B signalling pathway and amelioration of ER stress. MANF also increased the proliferation of primary human beta cells twofold when TGF-beta signalling was inhibited (p <0.01). Our studies show that exogenous MANF protein can provide protection to human beta cells against death induced by inflammatory stress. The antiapoptotic and mitogenic properties of MANF make it a potential therapeutic agent for beta cell protection.