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1. POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies

Author

Smallwood, Kelly, Watt, Kristin E.N., Ide, Satoru, Baltrunaite, Kristina, Brunswick, Chad, Inskeep, Katherine, Capannari, Corrine, Adam, Margaret P., Begtrup, Amber, Bertola, Debora R., Demmer, Laurie, Demo, Erin, Devinsky, Orrin, Gallagher, Emily R., Guillen Sacoto, Maria J., Jech, Robert, Keren, Boris, Kussmann, Jennifer, Ladda, Roger, Lansdon, Lisa A., Lunke, Sebastian, Mardy, Anne, McWalters, Kirsty, Person, Richard, Raiti, Laura, Saitoh, Noriko, Saunders, Carol J., Schnur, Rhonda, Skorvanek, Matej, Sell, Susan L., Slavotinek, Anne, Sullivan, Bonnie R., Stark, Zornitza, Symonds, Joseph D., Wenger, Tara, Weber, Sacha, Whalen, Sandra, White, Susan M., Winkelmann, Juliane, Zech, Michael, Zeidler, Shimriet, Maeshima, Kazuhiro, Stottmann, Rolf W., Trainor, Paul A., Weaver, K. Nicole, and Clinical Genetics

Subjects
Genetics, Genetics (clinical)
Abstract

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.

Published
2023

2. A country-level analysis comparing hospital capacity and utilisation during the first COVID-19 wave across Europe

Author

Nimptsch Ulrike, Panteli Dimitra, Rombey Tanja, Winkelmann Juliane, Eckhardt Helene, Busse Reinhard, Reichebner Christoph, and Berger Elke

Subjects
medicine.medical_specialty, DE, Germany, Critical Care, Coronavirus disease 2019 (COVID-19), Article, OWiD, Our World in Data, DK, Denmark, Country level, PPE, Personal Protective Equipment, BE, Belgium, ICU, Intensive Care Unit, Intensive care, Acute care, Pandemic, medicine, Humans, IT, Italy, hospital capacity, HSRM, Health System Response Monitor, hospital utilisation, Pandemics, intensive care, NL, The Netherlands, Surge Capacity, SARS-CoV-2, Health Policy, IT-25, Lombardy, COVID-19, GR, Greece, Bed capacity, Hospitals, Europe, Intensive Care Units, Hospital Bed Capacity, Emergency medicine, UK, United Kingdom, Business, IE, Ireland, NO, Norway, Hospital stay, ICU surge capacity
Abstract

Background : The exponential increase in SARS-CoV-2 infections during the first wave of the pandemic created an extraordinary overload and demand on hospitals, especially intensive care units (ICUs), across Europe. European countries have implemented different measures to address the surge ICU capacity, but little is known about the extent. The aim of this paper is to compare the rates of hospitalised COVID-19 patients in acute and ICU care and the levels of national surge capacity for intensive care beds across 16 European countries and Lombardy region during the first wave of the pandemic (28 February to 31 July). Methods : For this country level analysis, we used data on SARS-CoV-2 cases, current and/or cumulative hospitalised COVID-19 patients and current and/or cumulative COVID-19 patients in ICU care. To analyse whether capacities were exceeded, we also retrieved information on the numbers of hospital beds, and on (surge) capacity of ICU beds during the first wave of the COVID-19 pandemic from the COVID-19 Health System Response Monitor (HSRM). Treatment days and mean length of hospital stay were calculated to assess hospital utilisation. Results : Hospital and ICU capacity varied widely across countries. Our results show that utilisation of acute care bed capacity by patients with COVID-19 did not exceed 38.3% in any studied country. However, the Netherlands, Sweden, and Lombardy would not have been able to treat all patients with COVID-19 requiring intensive care during the first wave without an ICU surge capacity. Indicators of hospital utilisation were not consistently related to the number of SARS-CoV-2 infections. The mean number of hospital days associated with one SARS-CoV-2 case ranged from 1∙3 (Norway) to 11∙8 (France). Conclusion : In many countries, the increase in ICU capacity was important to accommodate the high demand for intensive care during the first COVID-19 wave.

Published
2022

3. Relationship of serum beta-synuclein with blood biomarkers and brain atrophy

Author

Oeckl, Patrick, Anderl-Straub, Sarah, Kornhuber, Johannes, Landwehrmeyer, Bernhard, Lauer, Martin, Prudlo, Johannes, Schneider, Anja, Schroeter, Matthias L, Steinacker, Petra, Volk, Alexander E, Wagner, Matias, Winkelmann, Juliane, Danek, Adrian, Wiltfang, Jens, Ludolph, Albert C, Otto, Markus, Consortium, FTLD, Diehl-Schmid, Janine, Fassbender, Klaus, Fliessbach, Klaus, Halbgebauer, Steffen, Huppertz, Hans-Jürgen, Jahn, Holger, and Kassubek, Jan

Subjects
RESEARCH ARTICLE, RESEARCH ARTICLES, Alzheimer's disease, beta-synuclein, blood biomarker, brain atrophy, dementia, frontotemporal lobar degeneration, FTLD, NfL, p-tau181, synaptic degeneration, Epidemiology, tau Proteins, Cellular and Molecular Neuroscience, pathology [Alzheimer Disease], Developmental Neuroscience, pathology [Brain], Humans, ddc:610, pathology [Atrophy], Amyloid beta-Peptides, pathology [Frontotemporal Lobar Degeneration], Health Policy, ddc, Psychiatry and Mental health, Frontotemporal Dementia, Neurology (clinical), Geriatrics and Gerontology, Biomarkers
Abstract

Background: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD).Methods: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores.Results: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy.Discussion: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations.Highlights: Blood beta-synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes. Blood beta-synuclein correlates with temporal brain atrophy in AD. Blood beta-synuclein correlates with cognitive impairment in AD. The pattern of blood beta-synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p-tau181) and neurofilament light (NfL).

Published
2022

4. Additional file 1 of Exploring variation of coverage and access to dental care for adults in 11 European countries: a vignette approach

Author

Winkelmann, Juliane, G��mez Rossi, Jes��s, Schwendicke, Falk, Dimova, Antoniya, Atanasova, Elka, Habicht, Triin, Kasekamp, Kaija, Gandr��, Coralie, Or, Zeynep, McAuliffe, ��na, Murauskiene, Liubove, Kroneman, Madelon, de Jong, Judith, Kowalska-Bobko, Iwona, Badora-Musia��, Katarzyna, Motyl, Sylwia, Figueiredo Augusto, Gon��alo, Pa��itn��, Peter, Kandilaki, Daniela, L��ffler, Lubica, Lundgren, Carl, Janl��v, Nils, van Ginneken, Ewout, and Panteli, Dimitra

Abstract

Additional file 1. Supplementary tables 1���4.

Published
2022
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5. KMT2B Is Selectively Required for Neuronal Transdifferentiation, and Its Loss Exposes Dystonia Candidate Genes

Author

Barbagiovanni, Giulia, Germain, Pierre Luc, Zech, Michael, Atashpaz, Sina, Lo Riso, Pietro, D'Antonio-Chronowska, Agnieszka, Tenderini, Erika, Caiazzo, Massimiliano, Boesch, Sylvia, Jech, Robert, Haslinger, Bernhard, Broccoli, Vania, Stewart, Adrian Francis, Winkelmann, Juliane, Testa, Giuseppe, Afd Pharmaceutics, Pharmaceutics, Barbagiovanni, Giulia, Germain, Pierre-Luc, Zech, Michael, Atashpaz, Sina, Lo Riso, Pietro, D'Antonio-Chronowska, Agnieszka, Tenderini, Erika, Caiazzo, Massimiliano, Boesch, Sylvia, Jech, Robert, Haslinger, Bernhard, Broccoli, Vania, Stewart, Adrian Franci, Winkelmann, Juliane, Testa, Giuseppe, Afd Pharmaceutics, and Pharmaceutics

Subjects
0301 basic medicine, Candidate gene, Histone H3 Lysine 4, mouse embryonic fibroblasts, transdifferentiation, Biochemistry, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, lcsh:QH301-705.5, Transcription factor, myocyte, Dystonia, induced neuronal cells, epigenetics, biology, Biochemistry, Genetics and Molecular Biology(all), Transdifferentiation, KMT2B, Epigenome, myocytes, medicine.disease, histone H3 lysine 4 methylation, Cell biology, induced neuronal cell, cell fate conversion, mouse embryonic fibroblast, ASCL1, 030104 developmental biology, KMT2A, lcsh:Biology (General), biology.protein, MLL2, dystonia, epigenetic, Genetics and Molecular Biology(all)
Abstract

Transdifferentiation of fibroblasts into induced neuronal cells (iNs) by the neuron-specific transcription factors Brn2, Myt1l, and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress regarding the transcriptional hierarchy underlying transdifferentiation, the enablers of the concomitant epigenome resetting remain to be elucidated. Here, we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and combined inactivation. We found that Kmt2b, whose human homolog’s mutations cause dystonia, is selectively required for iN conversion through suppression of the alternative myocyte program and induction of neuronal maturation genes. The identification of KMT2B-vulnerable targets allowed us, in turn, to expose, in a cohort of 225 patients, 45 unique variants in 39 KMT2B targets, which represent promising candidates to dissect the molecular bases of dystonia., Cell Reports, 25 (4), ISSN:2666-3864, ISSN:2211-1247

Published
2018

6. Plasma Proteomics of Renal Function: A Transethnic Meta-Analysis and Mendelian Randomization Study

Author

Matías-García, Pamela R, Wilson, Rory, Guo, Qi, Zaghlool, Shaza B, Eales, James M, Xu, Xiaoguang, Charchar, Fadi J, Dormer, John, Maalmi, Haifa, Schlosser, Pascal, Elhadad, Mohamed A, Nano, Jana, Sharma, Sapna, Peters, Annette, Fornoni, Alessia, Mook-Kanamori, Dennis O, Winkelmann, Juliane, Danesh, John, Di Angelantonio, Emanuele, Ouwehand, Willem H, Watkins, Nicholas A, Roberts, David J, Petrera, Agnese, Graumann, Johannes, Koenig, Wolfgang, Hveem, Kristian, Jonasson, Christian, Köttgen, Anna, Butterworth, Adam, Prunotto, Marco, Hauck, Stefanie M, Herder, Christian, Suhre, Karsten, Gieger, Christian, Tomaszewski, Maciej, Teumer, Alexander, Waldenberger, Melanie, Human Kidney Tissue Resource, Matías-García, Pamela R [0000-0002-3906-5405], Wilson, Rory [0000-0001-6135-3764], Schlosser, Pascal [0000-0002-8460-0462], Elhadad, Mohamed A [0000-0002-6758-8369], Petrera, Agnese [0000-0002-0583-6195], Graumann, Johannes [0000-0002-3015-5850], Köttgen, Anna [0000-0002-4671-3714], Prunotto, Marco [0000-0002-0203-0129], Hauck, Stefanie M [0000-0002-1630-6827], Waldenberger, Melanie [0000-0003-0583-5093], and Apollo - University of Cambridge Repository

Subjects
glomerular filtration rate, genetic epidemiology, plasma proteomics, biomarker discovery, Mendelian randomization, gene expression, epidemiology and outcomes, testican-2, chronic kidney disease
Abstract

BACKGROUND: Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. METHODS: A cross-sectional study of 993 plasma proteins among 2882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified transethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR. RESULTS: In total, 57 plasma proteins were associated with eGFR, including one novel protein. Of these, 23 were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. CONCLUSIONS: In a discovery-replication setting, we identified 57 proteins transethnically associated with eGFR. The revealed causal relationships are an important stepping stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.

Published
2021

7. Additional file 1 of Methylation status of nc886 epiallele reflects periconceptional conditions and is associated with glucose metabolism through nc886 RNAs

Author

Marttila, Saara, Viiri, Leena E., Mishra, Pashupati P., Kühnel, Brigitte, Matias-Garcia, Pamela R., Lyytikäinen, Leo-Pekka, Ceder, Tiina, Mononen, Nina, Rathmann, Wolfgang, Winkelmann, Juliane, Peters, Annette, Kähönen, Mika, Hutri-Kähönen, Nina, Juonala, Markus, Aalto-Setälä, Katriina, Raitakari, Olli, Lehtimäki, Terho, Waldenberger, Melanie, and Raitoharju, Emma

Abstract

Additional file 1. Supplementary Figures S1-6, Supplementary Tables S1-3 and S11-13 and Supplementary materials and methods.

Published
2021
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8. Additional file 3 of DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function

Author

Mat��as-Garc��a, Pamela R., Ward-Caviness, Cavin K., Raffield, Laura M., Gao, Xu, Zhang, Yan, Wilson, Rory, G��o, X��n, Nano, Jana, Bostom, Andrew, Colicino, Elena, Correa, Adolfo, Coull, Brent, Eaton, Charles, Hou, Lifang, Just, Allan C., Kunze, Sonja, Lange, Leslie, Lange, Ethan, Lin, Xihong, Liu, Simin, Nwanaji-Enwerem, Jamaji C., Reiner, Alex, Shen, Jincheng, Sch��ttker, Ben, Vokonas, Pantel, Zheng, Yinan, Young, Bessie, Schwartz, Joel, Horvath, Steve, Lu, Ake, Whitsel, Eric A., Koenig, Wolfgang, Adamski, Jerzy, Winkelmann, Juliane, Brenner, Hermann, Baccarelli, Andrea A., Gieger, Christian, Peters, Annette, Franceschini, Nora, and Waldenberger, Melanie

Abstract

Additional file 3: Notes including additional information on sensitivity analyses, the derivation of the DNAm-based predictors, cohort-specific details (background and study design, as well as data collection and pre-processing), and all legends to supplemental tables and figures.

Published
2021
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10. Additional file 2 of Impact of BMI and waist circumference on epigenome-wide DNA methylation and identification of epigenetic biomarkers in blood: an EWAS in multi-ethnic Asian individuals

Author

Chen, Yuqing, Kassam, Irfahan, Lau, Suk Hiang, Kooner, Jaspal S., Wilson, Rory, Peters, Annette, Winkelmann, Juliane, Chambers, John C., Chow, Vincent T., Khor, Chiea Chuen, van Dam, Rob M., Teo, Yik-Ying, Loh, Marie, and Sim, Xueling

Abstract

Additional file 2: Figure S1. Sensitivity analysis of control probes principal components analysis. The first five principal components were included in regression models.

Published
2021
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11. DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function

Author

Matías-García, Pamela R., Ward-Caviness, Cavin K., Raffield, Laura M., Gao, Xu, Zhang, Yan, Wilson, Rory, Gào, Xīn, Nano, Jana, Bostom, Andrew, Colicino, Elena, Correa, Adolfo, Coull, Brent, Eaton, Charles, Hou, Lifang, Just, Allan C., Kunze, Sonja, Lange, Leslie, Lange, Ethan, Lin, Xihong, Liu, Simin, Nwanaji-Enwerem, Jamaji C., Reiner, Alex, Shen, Jincheng, Schöttker, Ben, Vokonas, Pantel, Zheng, Yinan, Young, Bessie, Schwartz, Joel, Horvath, Steve, Lu, Ake, Whitsel, Eric A., Koenig, Wolfgang, Adamski, Jerzy, Winkelmann, Juliane, Brenner, Hermann, Baccarelli, Andrea A., Gieger, Christian, Peters, Annette, Franceschini, Nora, and Waldenberger, Melanie

Subjects
Male, Aging, Research, Serum urate, Epigenetic age acceleration, Aging, Premature, DNA Methylation, Middle Aged, Kidney function, Humans, Female, Renal Insufficiency, Glomerular filtration rate, Mortality, DNAm age, UACR, Aged
Abstract

Background The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. Results We identified 23 significant associations in our large trans-ethnic meta-analysis (p

Published
2021
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12. Additional file 2 of DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function

Author

Mat��as-Garc��a, Pamela R., Ward-Caviness, Cavin K., Raffield, Laura M., Gao, Xu, Zhang, Yan, Wilson, Rory, G��o, X��n, Nano, Jana, Bostom, Andrew, Colicino, Elena, Correa, Adolfo, Coull, Brent, Eaton, Charles, Hou, Lifang, Just, Allan C., Kunze, Sonja, Lange, Leslie, Lange, Ethan, Lin, Xihong, Liu, Simin, Nwanaji-Enwerem, Jamaji C., Reiner, Alex, Shen, Jincheng, Sch��ttker, Ben, Vokonas, Pantel, Zheng, Yinan, Young, Bessie, Schwartz, Joel, Horvath, Steve, Lu, Ake, Whitsel, Eric A., Koenig, Wolfgang, Adamski, Jerzy, Winkelmann, Juliane, Brenner, Hermann, Baccarelli, Andrea A., Gieger, Christian, Peters, Annette, Franceschini, Nora, and Waldenberger, Melanie

Abstract

Additional file 2: Figures S1���S7 showing forest plots for all significant associations not presented in the main figures, as well as secondary traits (categorical MRS), comparison of MRS and DNAmAA effect sizes across renal traits.

Published
2021
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13. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Author

Bryant, Laura, Li, Dong, Cox, Samuel G, Marchione, Dylan, Joiner, Evan F, Wilson, Khadija, Janssen, Kevin, Lee, Pearl, March, Michael E, Nair, Divya, Sherr, Elliott, Fregeau, Brieana, Wierenga, Klaas J, Wadley, Alexandrea, Mancini, Grazia MS, Powell-Hamilton, Nina, van de Kamp, Jiddeke, Grebe, Theresa, Dean, John, Ross, Alison, Crawford, Heather P, Powis, Zoe, Cho, Megan T, Willing, Marcia C, Manwaring, Linda, Schot, Rachel, Nava, Caroline, Afenjar, Alexandra, Lessel, Davor, Wagner, Matias, Klopstock, Thomas, Winkelmann, Juliane, Catarino, Claudia B, Retterer, Kyle, Schuette, Jane L, Innis, Jeffrey W, Pizzino, Amy, Lüttgen, Sabine, Denecke, Jonas, Strom, Tim M, Monaghan, Kristin G, DDD Study, Yuan, Zuo-Fei, Dubbs, Holly, Bend, Renee, Lee, Jennifer A, Lyons, Michael J, Hoefele, Julia, Günthner, Roman, Reutter, Heiko, Keren, Boris, Radtke, Kelly, Sherbini, Omar, Mrokse, Cameron, Helbig, Katherine L, Odent, Sylvie, Cogne, Benjamin, Mercier, Sandra, Bezieau, Stephane, Besnard, Thomas, Kury, Sebastien, Redon, Richard, Reinson, Karit, Wojcik, Monica H, Õunap, Katrin, Ilves, Pilvi, Innes, A Micheil, Kernohan, Kristin D, Care4Rare Canada Consortium, Costain, Gregory, Meyn, M Stephen, Chitayat, David, Zackai, Elaine, Lehman, Anna, Kitson, Hilary, CAUSES Study, Martin, Martin G, Martinez-Agosto, Julian A, Undiagnosed Diseases Network, Nelson, Stan F, Palmer, Christina GS, Papp, Jeanette C, Parker, Neil H, Sinsheimer, Janet S, Vilain, Eric, Wan, Jijun, Yoon, Amanda J, Zheng, Allison, Brimble, Elise, Ferrero, Giovanni Battista, Radio, Francesca Clementina, Carli, Diana, Barresi, Sabina, Brusco, Alfredo, Tartaglia, Marco, Thomas, Jennifer Muncy, Umana, Luis, Weiss, Marjan M, Gotway, Garrett, and Stuurman, KE

Subjects
Pediatric Research Initiative, Care4Rare Canada Consortium, Human Genome, Neurodegenerative Diseases, Forkhead Transcription Factors, Undiagnosed Diseases Network, Zebrafish Proteins, Histones, CAUSES Study, Rare Diseases, Genetics, Animals, Humans, 2.1 Biological and endogenous factors, Aetiology, Zebrafish, Germ-Line Mutation, DDD Study, Biotechnology, Cancer
Abstract

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

Published
2020

14. DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function

Author

Matías-García, Pamela R., Ward-Caviness, Cavin K., Raffield, Laura M., Gao, Xu, Zhang, Yan, Wilson, Rory, Gào, Xīn, Nano, Jana, Bostom, Andrew, Colicino, Elena, Correa, Adolfo, Coull, Brent, Eaton, Charles, Hou, Lifang, Just, Allan C., Kunze, Sonja, Lange, Leslie, Lange, Ethan, Lin, Xihong, Liu, Simin, Nwanaji-Enwerem, Jamaji C., Reiner, Alex, Shen, Jincheng, Schöttker, Ben, Vokonas, Pantel, Zheng, Yinan, Young, Bessie, Schwartz, Joel, Horvath, Steve, Lu, Ake, Whitsel, Eric A., Koenig, Wolfgang, Adamski, Jerzy, Winkelmann, Juliane, Brenner, Hermann, Baccarelli, Andrea A., Gieger, Christian, Peters, Annette, Franceschini, Nora, and Waldenberger, Melanie

Subjects
ddc
Published
2020

15. Methylation status of nc886 epiallele reflects periconceptional conditions and is associated with glucose metabolism through nc886 RNAs

Author

Marttila, Saara, Viiri, Leena E., Mishra, Pashupati P., Kühnel, Brigitte, Matias-Garcia, Pamela R., Lyytikäinen, Leo-Pekka, Ceder, Tiina, Mononen, Nina, Rathmann, Wolfgang, Winkelmann, Juliane, Peters, Annette, Kähönen, Mika, Hutri-Kähönen, Nina, Juonala, Markus, Aalto-Setälä, Katriina, Raitakari, Olli, Lehtimäki, Terho, Waldenberger, Melanie, and Raitoharju, Emma

Subjects
ddc
Published
2020

16. Loss‐of‐Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities

Author

Steel, Dora, Zech, Michael, Zhao, Chen, Barwick, Katy E. S., Burke, Derek, Demailly, Diane, Kumar, Kishore R., Zorzi, Giovanna, Nardocci, Nardo, Kaiyrzhanov, Rauan, Wagner, Matias, Iuso, Arcangela, Berutti, Riccardo, Škorvánek, Matej, Necpál, Ján, Davis, Ryan, Wiethoff, Sarah, Mankad, Kshitij, Sudhakar, Sniya, Ferrini, Arianna, Sharma, Suvasini, Kamsteeg, Erik‐Jan, Tijssen, Marina A., Verschuuren, Corien, Egmond, Martje E., Flowers, Joanna M., McEntagart, Meriel, Tucci, Arianna, Coubes, Philippe, Bustos, Bernabe I., Gonzalez‐Latapi, Paulina, Tisch, Stephen, Darveniza, Paul, Gorman, Kathleen M., Peall, Kathryn J., Bötzel, Kai, Koch, Jan C., Kmieć, Tomasz, Plecko, Barbara, Boesch, Sylvia, Haslinger, Bernhard, Jech, Robert, Garavaglia, Barbara, Wood, Nick, Houlden, Henry, Gissen, Paul, Lubbe, Steven J., Sue, Carolyn M., Cif, Laura, Mencacci, Niccolò E., Anderson, Glenn, Kurian, Manju A., and Winkelmann, Juliane

Subjects
ddc
Published
2019

17. Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

Author

Götzl, Julia K, Brendel, Matthias, Werner, Georg, Parhizkar, Samira, Sebastian Monasor, Laura, Kleinberger, Gernot, Colombo, Alessio‐Vittorio, Deussing, Maximilian, Wagner, Matias, Winkelmann, Juliane, Diehl‐Schmid, Janine, Levin, Johannes, Fellerer, Katrin, Reifschneider, Anika, Bultmann, Sebastian, Bartenstein, Peter, Rominger, Axel, Tahirovic, Sabina, Smith, Scott T, Madore, Charlotte, Butovsky, Oleg, Capell, Anja, and Haass, Christian

Subjects
ddc
Published
2018

18. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis

Author

Goyette, Philippe, Boucher, Gabrielle, Mallon, Dermot, Ellinghaus, Eva, Jostins, Luke, Huang, Hailiang, Ripke, Stephan, Gusareva, Elena S., Annese, Vito, Hauser, Stephen L., Oksenberg, Jorge R., Thomsen, Ingo, Leslie, Stephen, Daly, Mark J., Van Steen, Kristel, Duerr, Richard H., Barrett, Jeffrey C., Mcgovern, Dermot P. B., Schumm, L. Philip, Traherne, James A., Carrington, Mary N., Kosmoliaptsis, Vasilis, Karlsen, Tom H., Franke, Andre, Rioux, John D., Abraham, Clara, Achkar, Jean Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Anderson, Carl A., Andrews, Jane M., Aumais, Guy, Baidoo, Leonard, Baldassano, Robert N., Balschun, Tobias, Bampton, Peter A., Barclay, Murray, Bayless, Theodore M., Bethge, Johannes, Bis, Joshua C., Bitton, Alain, Brand, Stephan, Brant, Steven R., Buning, Carsten, Chew, Angela, Cho, Judy H., Cleynen, Isabelle, Cohain, Ariella, Croft, Anthony, D'Amato, Mauro, Danese, Silvio, De Jong, Dirk, De Vos, Martine, Denapiene, Goda, Denson, Lee A., Devaney, Kathy L., Dewit, Olivier, D'Inca, Renata, Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Essers, Jonah, Ferguson, Lynnette R., Festen, Eleonora A., Fleshner, Philip, Florin, Tim, Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jurgen, Green, Todd, Griffiths, Anne M., Guthery, Stephen L., Hakonarson, Hakon, Halfvarson, Jonas, Hanigan, Katherine, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hayward, Nicholas K., Hedl, Matija, Henderson, Paul, Xinli, Hu, Hui, Ken Y., Imielinski, Marcin, Ippoliti, Andrew, Jonaitis, Laimas, Kennedy, Nicholas A., Khan, Mohammed Azam, Kiudelis, Gediminas, Kugathasan, Subra, Kupcinskas, Limas, Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lee, James C., Lees, Charlie W., Leja, Marcis, Van Limbergen, Johan, Lionetti, Paolo, Liu, Jimmy Z., Louis, Edouard, Mahy, Gillian, Mansfield, John, Massey, Dunecan, Mathew, Christopher G., Milgrom, Raquel, Mitrovic, Mitja, Montgomery, Grant, Mowat, Craig, Newman, Wwilliam, Aylwin, Ng, Siew C., Ng, Evelyn Ng, Sok Meng, Nikolaus, Susanna, Ning, Kaida, Nothen, Markus, Oikonomou, Ioannis, Palmieri, Orazio, Parkes, Miles, Phillips, Anne, Ponsioen, Cyriel Y., Potocnik, Uros, Prescott, Natalie J., Proctor, Deborah D., Radford Smith, Graham, Rahier, Jean Francois, Raychaudhur, Soumya, Regueiro, Miguel, Rieder, Florian, Roberts, Rebecca, Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schadt, Eric E., Schreiber, Stefan, Scott, Regan, Seielstad, Mark, Sharma, Yashoda, Silverberg, Mark S., Simms, Lisa A., Skieceviciene, Jurgita, Spain, Sarah L., Steinhart, A. Hillary, Stempak, Joanne M., Stronati, Laura, Sventoraityte, Jurgita, Targan, Stephan R., Taylor, Kirstin M., Ter Velde, Anje, Theatre, Emilie, Torkvist, Leif, Tremelling, Mark, Van Der Meulen, Andrea, Van Sommeren, Suzanne, Vasiliauskas, Eric, Vermeire, Severine, Verspaget, Hein W., Walters, Thomas, Wwang, Kai, Wwang, Ming Hsi, Wweersma, Rinse K., Wei, Zhi, Whiteman, David, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Xavier, Ramnik J., Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhang, Hu, Zhang, Wwei, Zhao, Hongyu, Zhao, Zhen Z., Gastroenterology and Hepatology, Traherne, James [0000-0002-6003-8559], Kosmoliaptsis, Vasilis [0000-0001-7298-1387], and Apollo - University of Cambridge Repository

Subjects
Heterozygote, Genotype, Genotyping Techniques, Genetic Linkage, Ulcerative, Human leukocyte antigen, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, Primary sclerosing cholangitis, Major Histocompatibility Complex, Alleles, Chromosome Mapping, Colitis, Ulcerative, Crohn Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DRB1 Chains, Humans, Inflammatory Bowel Diseases, Phenotype, Genetics, medicine, HLA-DR, Polymorphism, Colitis, HLA-DRB1, Crohn's disease, Single Nucleotide, medicine.disease, Ulcerative colitis, digestive system diseases, Immunology, biology.protein
Abstract

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

Published
2015

19. Meis1: effects on motor phenotypes and the sensorimotor system in mice

Author

Salminen, Aaro V, Garrett, Lillian, Klingenspor, Martin, Klopstock, Thomas, Wolf, Eckhard, Zimmer, Andreas, Gailus-Durner, Valérie, Torres, Miguel, Fuchs, Helmut, Hrabě de Angelis, Martin, Wurst, Wolfgang, Hölter, Sabine M, Schormair, Barbara, Winkelmann, Juliane, Rozman, Jan, Giesert, Florian, Niedermeier, Kristina M, Becker, Lore, Rathkolb, Birgit, Rácz, Ildikó, Consortium, German Mouse Clinic, Emil Aaltosen Säätiö (Finlandia), Unión Europea. Comisión Europea, Federal Ministry of Education & Research (Alemania), and Deutsche Forschungsgemeinschaft (Alemania)

Subjects
0301 basic medicine, Male, drug effects [Sensory Gating], RESTLESS LEGS SYNDROME, Medicine (miscellaneous), lcsh:Medicine, drug effects [Neurogenesis], Receptors, Dopamine, EXPRESSION LEVELS, 0302 clinical medicine, Pramipexole, Immunology and Microbiology (miscellaneous), drug effects [Behavior, Animal], Restless legs syndrome, blood [Ferritins], Myeloid Ecotropic Viral Integration Site 1 Protein, Prepulse inhibition, RISK, Sex Characteristics, drug effects [Prepulse Inhibition], Neurogenesis, Dopaminergic, metabolism [Dopaminergic Neurons], deficiency [Myeloid Ecotropic Viral Integration Site 1 Protein], Temperature, Transferrin, pharmacology [Dopamine Agonists], Phenotype, Dopamine Agonists, Female, Haploinsufficiency, HOMEOPROTEINS, Research Article, medicine.drug, lcsh:RB1-214, Agonist, medicine.medical_specialty, GENES, medicine.drug_class, Iron, PATHOPHYSIOLOGY, Neuroscience (miscellaneous), Biology, PREPULSE INHIBITION, General Biochemistry, Genetics and Molecular Biology, Mouse model, NEUROGENESIS, 03 medical and health sciences, metabolism [Sensorimotor Cortex], Internal medicine, ddc:570, mental disorders, genetics [Haploinsufficiency], medicine, lcsh:Pathology, Animals, metabolism [Aging], GENOME-WIDE ASSOCIATION, drug effects [Nociception], Sensorimotor system, drug effects [Motor Activity], lcsh:R, Meis1, Mouse Model, Prepulse Inhibition, Restless Legs Syndrome, Sensorimotor System, metabolism [Myeloid Ecotropic Viral Integration Site 1 Protein], medicine.disease, metabolism [Receptors, Dopamine], SLEEP, Olfactory bulb, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, metabolism [Transferrin], Ferritins, drug effects [Sensorimotor Cortex], blood [Iron], pathology [Sensorimotor Cortex], 030217 neurology & neurosurgery, Meis1 protein, mouse
Abstract

MEIS1 encodes a developmental transcription factor and has been linked to restless legs syndrome (RLS) in genome-wide association studies. RLS is a movement disorder leading to severe sleep reduction and has a substantial impact on the quality of life of patients. In genome-wide association studies, MEIS1 has consistently been the gene with the highest effect size and functional studies suggest a disease-relevant downregulation. Therefore, haploinsufficiency of Meis1 could be the system with the most potential for modeling RLS in animals. We used heterozygous Meis1-knockout mice to study the effects of Meis1 haploinsufficiency on mouse behavioral and neurological phenotypes, and to relate the findings to human RLS. We exposed the Meis1-deficient mice to assays of motor, sensorimotor and cognitive ability, and assessed the effect of a dopaminergic receptor 2/3 agonist commonly used in the treatment of RLS. The mutant mice showed a pattern of circadian hyperactivity, which is compatible with human RLS. Moreover, we discovered a replicable prepulse inhibition (PPI) deficit in the Meis1-deficient animals. In addition, these mice were hyposensitive to the PPI-reducing effect of the dopaminergic receptor agonist, highlighting a role of Meis1 in the dopaminergic system. Other reported phenotypes include enhanced social recognition at an older age that was not related to alterations in adult olfactory bulb neurogenesis previously shown to be implicated in this behavior. In conclusion, the Meis1-deficient mice fulfill some of the hallmarks of an RLS animal model, and revealed the role of Meis1 in sensorimotor gating and in the dopaminergic systems modulating it., Summary: Loss of Meis1 results in motor restlessness in mice, a phenotype resembling human restless legs syndrome, as well as altered sensorimotor gating and improved social discrimination memory.

Published
2017

20. Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum

Author

Rothwell, Simon, Cooper, Robert G., Lundberg, Ingrid E., Gregersen, Peter K., Hanna, Michael G., Machado, Pedro M., Herbert, Megan K., Pruijn, Ger J. M., Lilleker, James B., Roberts, Mark, Bowes, John, Seldin, Michael F., Vencovsky, Jiri, Danko, Katalin, Limaye, Vidya, Selva‐O'Callaghan, Albert, Platt, Hazel, Molberg, Øyvind, Benveniste, Olivier, Radstake, Timothy R. D. J., Doria, Andrea, De Bleecker, Jan, De Paepe, Boel, Gieger, Christian, Meitinger, Thomas, Winkelmann, Juliane, Amos, Christopher I., Ollier, William E., Padyukov, Leonid, Lee, Annette T., Lamb, Janine A., Chinoy, Hector, Denton, Christopher, Gheorghe, Karina, Hilton‐Jones, David, Kiely, Patrick, and Mann, Herman

Subjects
musculoskeletal diseases, Receptors, CCR5, Myositis, Bio-Molecular Chemistry, Orvostudományok, Klinikai orvostudományok, White People, Myositis, Inclusion Body, Journal Article, Humans, Genetic Predisposition to Disease, Chromosomes, Human, Pair 3, Age of Onset, Amino Acids, Muscle, Skeletal, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Genetic Association Studies, Autoantibodies, HLA-DRB1 Chains
Abstract

OBJECTIVE: Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is unknown, genetic factors may influence disease susceptibility. To determine genetic factors contributing to the etiology of IBM, we conducted the largest genetic association study of the disease to date, investigating immune-related genes using the Immunochip. METHODS: A total of 252 Caucasian patients with IBM were recruited from 11 countries through the Myositis Genetics Consortium and compared with 1,008 ethnically matched controls. Classic HLA alleles and amino acids were imputed using SNP2HLA. RESULTS: The HLA region was confirmed as the most strongly associated region in IBM (P = 3.58 × 10(-33) ). HLA imputation identified 3 independent associations (with HLA-DRB1*03:01, DRB1*01:01, and DRB1*13:01), although the strongest association was with amino acid positions 26 and 11 of the HLA-DRB1 molecule. No association with anti-cytosolic 5'-nucleotidase 1A-positive status was found independent of HLA-DRB1*03:01. There was no association of HLA genotypes with age at onset of IBM. Three non-HLA regions reached suggestive significance, including the chromosome 3 p21.31 region, an established risk locus for autoimmune disease, where a frameshift mutation in CCR5 is thought to be the causal variant. CONCLUSION: This is the largest, most comprehensive genetic association study to date in IBM. The data confirm that HLA is the most strongly associated region and identifies novel amino acid associations that may explain the risk in this locus. These amino acid associations differentiate IBM from polymyositis and dermatomyositis and may determine properties of the peptide-binding groove, allowing it to preferentially bind autoantigenic peptides. A novel suggestive association within the chromosome 3 p21.31 region suggests a role for CCR5.

Published
2017

21. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Author

Benyamin, Beben, Esko, Tonu, Ried, Janina S, Radhakrishnan, Aparna, Vermeulen, Sita H, Traglia, Michela, Gögele, Martin, Anderson, Denise, Broer, Linda, Podmore, Clara, Luan, Jian'An, Kutalik, Zoltan, Sanna, Serena, van der Meer, Peter, Tanaka, Toshiko, Wang, Fudi, Westra, Harm Jan, Franke, Lude, Mihailov, Evelin, Milani, Lili, Hälldin, Jonas, Häldin, Jonas, Winkelmann, Juliane, Meitinger, Thomas, Thiery, Joachim, Peters, Annette, Waldenberger, Melanie, Rendon, Augusto, Jolley, Jennifer, Sambrook, Jennifer, Kiemeney, Lambertus A, Sweep, Fred C, Sala, Cinzia F, Schwienbacher, Christine, Pichler, Irene, Hui, Jennie, Demirkan, Ayse, Isaacs, Aaron, Amin, Najaf, Steri, Maristella, Waeber, Gérard, Verweij, Niek, Powell, Joseph E, Nyholt, Dale R, Heath, Andrew C, Madden, Pamela A. F, Visscher, Peter M, Wright, Margaret J, Montgomery, Grant W, Martin, Nicholas G, Hernandez, Dena, Bandinelli, Stefania, van der Harst, Pim, Uda, Manuela, Vollenweider, Peter, Scott, Robert A, Langenberg, Claudia, Wareham, Nicholas J, van Duijn, Cornelia, Beilby, John, Pramstaller, Peter P, Hicks, Andrew A, Ouwehand, Willem H, Oexle, Konrad, Gieger, Christian, Metspalu, Andres, Camaschella, Clara, Toniolo, Daniela, Swinkels, Dorine W, Whitfield, John B., PANICO, SALVATORE, Podmore, Clara [0000-0002-2452-8067], Luan, Jian'an [0000-0003-3137-6337], Rendon Restrepo, Augusto [0000-0001-8994-0039], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Ouwehand, Willem [0000-0002-7744-1790], Apollo - University of Cambridge Repository, Benyamin, Beben, Esko, Tonu, Ried, Janina S, Radhakrishnan, Aparna, Vermeulen, Sita H, Traglia, Michela, Gögele, Martin, Anderson, Denise, Broer, Linda, Podmore, Clara, Luan, Jian'An, Kutalik, Zoltan, Sanna, Serena, van der Meer, Peter, Tanaka, Toshiko, Wang, Fudi, Westra, Harm Jan, Franke, Lude, Mihailov, Evelin, Milani, Lili, Hälldin, Jona, Häldin, Jona, Winkelmann, Juliane, Meitinger, Thoma, Thiery, Joachim, Peters, Annette, Waldenberger, Melanie, Rendon, Augusto, Jolley, Jennifer, Sambrook, Jennifer, Kiemeney, Lambertus A, Sweep, Fred C, Sala, Cinzia F, Schwienbacher, Christine, Pichler, Irene, Hui, Jennie, Demirkan, Ayse, Isaacs, Aaron, Amin, Najaf, Steri, Maristella, Waeber, Gérard, Verweij, Niek, Powell, Joseph E, Nyholt, Dale R, Heath, Andrew C, Madden, Pamela A. F, Visscher, Peter M, Wright, Margaret J, Montgomery, Grant W, Martin, Nicholas G, Hernandez, Dena, Bandinelli, Stefania, van der Harst, Pim, Uda, Manuela, Vollenweider, Peter, Scott, Robert A, Langenberg, Claudia, Wareham, Nicholas J, van Duijn, Cornelia, Beilby, John, Pramstaller, Peter P, Hicks, Andrew A, Ouwehand, Willem H, Oexle, Konrad, Gieger, Christian, Metspalu, Andre, Camaschella, Clara, Toniolo, Daniela, Swinkels, Dorine W, Whitfield, John B., Panico, Salvatore, Internal Medicine, Epidemiology, Erasmus MC other, Benyamin, B, Esko, T, Ried, J, Radhakrishnan, A, Vermeulen, Sh, Traglia, M, Gogele, M, Anderson, D, Broer, L, Podmore, C, Luan, J, Kutalik, Z, Sanna, S, VAN DER MEER, P, Tanaka, T, Wang, F, Westra, Hj, Franke, L, Mihailov, E, Milani, L, Haldin, J, Winkelmann, J, Meitinger, T, Thiery, J., Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), InterAct Consortium, and Whitfield, John B

Subjects
FERRITIN LEVELS, General Physics and Astronomy, Transferrin/metabolism, Genome-wide association study, 0302 clinical medicine, Chromosomes, Human, Pair 7/genetics, Risk Factors, GENETIC-VARIANTS, Homeostasis, chemistry.chemical_classification, Genetics, TRANSFERRIN RECEPTOR 2, 0303 health sciences, education.field_of_study, Multidisciplinary, HFE HEREDITARY HEMOCHROMATOSIS, Transferrin, COMMON VARIANTS, Lipid, FOAM CELL-FORMATION, Polymorphism, Single Nucleotide/genetics, Lipids, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, ARNTL, Phenotype, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, CORONARY-ARTERY-DISEASE, Hemochromatosis, HFE Protein, Single Nucleotide/genetics, Chromosomes, Human, Pair 7, Human, Adult, Hemochromatosi, Iron, Reproducibility of Result, Transferrin receptor, Single-nucleotide polymorphism, Genetic Association Studie, Biology, Polymorphism, Single Nucleotide, Chromosomes, Article, General Biochemistry, Genetics and Molecular Biology, hemochromatosis, 03 medical and health sciences, Homeostasi, TOTAL MORTALITY, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, education, Iron/blood, Genetic Association Studies, 030304 developmental biology, Genetic association, Ferritin, Lipids/blood, Risk Factor, CIRCADIAN-RHYTHM, Hemochromatosis/blood, Reproducibility of Results, General Chemistry, Homeostasis/genetics, medicine.disease, Ferritins/metabolism, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Gene Expression Regulation, chemistry, Pair 7/genetics, Genetic Loci, Ferritins, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5]
Abstract

Contains fulltext : 137523.pdf (Publisher’s version ) (Open Access) Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P

Published
2014

22. Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up

Author

Zech, Michael, Boesch, Sylvia, Jochim, Angela, Weber, Sandrina, Meindl, Tobias, Schormair, Barbara, Wieland, Thomas, Lunetta, Christian, Sansone, Valeria, Messner, Michael, Mueller, Joerg, Ceballos Baumann, Andres, Strom, Tim M., Colombo, Roberto, Poewe, Werner, Haslinger, Bernhard, and Winkelmann, Juliane

Subjects
Adult, Male, Models, Molecular, DNA Mutational Analysis, Anoctamins, ANO3, Young Adult, Chloride Channels, Humans, Exome, ADCY5, Diagnostics, Dystonia, Neurology, Neurology (clinical), GTP Cyclohydrolase, Settore BIO/10 - BIOCHIMICA, Family Health, Nuclear Proteins, Middle Aged, DNA-Binding Proteins, Mutation, Female, Apoptosis Regulatory Proteins, Adenylyl Cyclases, Follow-Up Studies, Molecular Chaperones
Abstract

Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation.Clinical whole-exome sequencing coupled with bioinformatics analysis and detailed phenotyping of mutation carriers was performed on 16 consecutive cases with genetically undefined early-onset generalized dystonia. Candidate pathogenic variants were validated and tested for cosegregation. The whole-exome approach was complemented by analyzing 2 mutated yet unestablished causative genes in another 590 dystonia cases.Whole-exome sequencing detected clinically relevant mutations of known dystonia-related genes in 6 generalized dystonia cases (37.5%), among whom 3 had novel variants. Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently. Three genes (GCH1, THAP1, TOR1A) were associated with isolated generalized dystonia, whereas 2 (ANO3, ADCY5) gave rise to combined dystonia-myoclonus phenotypes. Follow-up screening of ANO3 and ADCY5 revealed a set of distinct variants of interest, the pathogenicity of which was supported by bioinformatics testing and cosegregation work.Our study identified whole-exome sequencing as an effective strategy for molecular diagnosis of early-onset generalized dystonia and offers insights into the heterogeneous genetic architecture of this condition. Furthermore, it provides confirmatory evidence for a dystonia-relevant role of ANO3 and ADCY5, both of which likely associate with a broader spectrum of dystonic expressions than previously thought. © 2016 International Parkinson and Movement Disorder Society.

Published
2016

23. Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies

Author

Ellinghaus, David, Zhang, Hu, Zeissig, Sebastian, Lipinski, Simone, Till, Andreas, Jiang, Tao, Stade, Björn, Bromberg, Yana, Ellinghaus, Eva, Keller, Andreas, Rivas, Manuel A, Skieceviciene, Jurgita, Doncheva, Nadezhda T, Liu, Xiao, Liu, Qing, Jiang, Fuman, Forster, Michael, Mayr, Gabriele, Albrecht, Mario, Häsler, Robert, Boehm, Bernhard O, Goodall, Jane, Berzuini, Carlo R, Lee, James, Andersen, Vibeke, Vogel, Ulla, Kupcinskas, Limas, Kayser, Manfred, Krawczak, Michael, Nikolaus, Susanna, Weersma, Rinse K, Ponsioen, Cyriel Y, Sans, Miquel, Wijmenga, Cisca, Strachan, David P, McArdle, Wendy L, Vermeire, Séverine, Rutgeerts, Paul, Sanderson, Jeremy D, Mathew, Christopher G, Vatn, Morten H, Wang, Jun, Nöthen, Markus M, Duerr, Richard H, Büning, Carsten, Brand, Stephan, Glas, Jürgen, Winkelmann, Juliane, Illig, Thomas, Latiano, Anna, Annese, Vito, Halfvarson, Jonas, D'Amato, Mauro, Daly, Mark J, Nothnagel, Michael, Karlsen, Tom H, Subramani, Suresh, Rosenstiel, Philip, Schreiber, Stefan, Parkes, Miles, and Franke, Andre

Subjects
Male, Crohn’s disease, quantitative reverse-transcription polymerase chain reaction, Ulcerative, Crohn's Disease, NF-κB, UC, Crohn Disease, expression quantitative trait locus, single nucleotide polymorphism, PBL, GWAS, 2.1 Biological and endogenous factors, Exome, single nucleotide variant, Aetiology, Whole-Exome Sequencing, WT, Nuclear Proteins, Single Nucleotide, interferon, Colitis, CD, Complex Disease, Female, Biotechnology, Adult, Adolescent, Quantitative Trait Loci, IBD, Clinical Sciences, SNP, IFN, eQTL, Autoimmune Disease, Paediatrics and Reproductive Medicine, Young Adult, Oral and Gastrointestinal, Toll-like receptor, inflammatory bowel disease, Clinical Research, TLR, SNV, Genetics, Humans, Genetic Predisposition to Disease, Inflammatory and Immune System, Polymorphism, ulcerative colitis, wild-type, Gastroenterology & Hepatology, PBMC, Human Genome, Neurosciences, qRT-PCR, peripheral blood lymphocyte, Repressor Proteins, nuclear factor κB, peripheral blood mononuclear cell, Case-Control Studies, Mutation, genome-wide association studies, Positive Regulatory Domain I-Binding Factor 1, Missense, Digestive Diseases, Genome-Wide Association Study
Abstract

Background & aimsGenome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.MethodsWe sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.ResultsWe identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.ConclusionsWe have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.

Published
2013

24. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

Author

Liu, Jimmy Z, Hov, Johannes Roksund, Folseraas, Trine, Ellinghaus, Eva, Rushbrook, Simon M, Doncheva, Nadezhda T, Andreassen, Ole A, Weersma, Rinse K, Weismüller, Tobias J, Eksteen, Bertus, Invernizzi, Pietro, Hirschfield, Gideon M, Gotthardt, Daniel Nils, Pares, Albert, Ellinghaus, David, Shah, Tejas, Juran, Brian D, Milkiewicz, Piotr, Rust, Christian, Schramm, Christoph, Müller, Tobias, Srivastava, Brijesh, Dalekos, Georgios, Nöthen, Markus M, Herms, Stefan, Winkelmann, Juliane, Mitrovic, Mitja, Braun, Felix, Ponsioen, Cyriel Y, Croucher, Peter JP, Sterneck, Martina, Teufel, Andreas, Mason, Andrew L, Saarela, Janna, Leppa, Virpi, Dorfman, Ruslan, Alvaro, Domenico, Floreani, Annarosa, Onengut-Gumuscu, Suna, Rich, Stephen S, Thompson, Wesley K, Schork, Andrew J, Næss, Sigrid, Thomsen, Ingo, Mayr, Gabriele, König, Inke R, Hveem, Kristian, Cleynen, Isabelle, Gutierrez-Achury, Javier, Ricaño-Ponce, Isis, van Heel, David, Björnsson, Einar, Sandford, Richard N, Durie, Peter R, Melum, Espen, Vatn, Morten H, Silverberg, Mark S, Duerr, Richard H, Padyukov, Leonid, Brand, Stephan, Sans, Miquel, Annese, Vito, Achkar, Jean-Paul, Boberg, Kirsten Muri, Marschall, Hanns-Ulrich, Chazouillères, Olivier, Bowlus, Christopher L, Wijmenga, Cisca, Schrumpf, Erik, Vermeire, Severine, Albrecht, Mario, UK-PSCSC Consortium, Rioux, John D, Alexander, Graeme, Bergquist, Annika, Cho, Judy, Schreiber, Stefan, Manns, Michael P, Färkkilä, Martti, Dale, Anders M, Chapman, Roger W, Lazaridis, Konstantinos N, International PSC Study Group, Franke, Andre, Anderson, Carl A, Karlsen, Tom H, International IBD Genetics Consortium, Sandford, Richard [0000-0002-7437-0560], and Apollo - University of Cambridge Repository

Subjects
endocrine system diseases, Genotyping Techniques, Cholangitis, UK-PSCSC Consortium, Chronic Liver Disease and Cirrhosis, Cholangitis, Sclerosing, International PSC Study Group, Autoimmune Disease, Medical and Health Sciences, digestive system, Polymorphism, Single Nucleotide, Sclerosing, Linkage Disequilibrium, Rare Diseases, Gene Frequency, Clinical Research, Risk Factors, 2.1 Biological and endogenous factors, Humans, Polymorphism, Aetiology, Digestive Diseases - (Gallbladder), Oligonucleotide Array Sequence Analysis, Liver Disease, digestive, oral, and skin physiology, Genetic Pleiotropy, Single Nucleotide, Biological Sciences, digestive system diseases, International IBD Genetics Consortium, Genetic Loci, Case-Control Studies, Digestive Diseases, Developmental Biology, Genome-Wide Association Study
Abstract

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

Published
2013

25. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Author

Jostins, Luke, Ripke, Stephan, Weersma, Rinse K., Duerr, Richard H., Mcgovern, Dermot P., Hui, Ken Y., Lee, James C., Philip Schumm, L., Sharma, Yashoda, Anderson, Carl A., Essers, Jonah, Mitrovic, Mitja, Ning, Kaida, Cleynen, Isabelle, Theatre, Emilie, Spain, Sarah L., Raychaudhuri, Soumya, Goyette, Philippe, Wei, Zhi, Abraham, Clara, Achkar, Jean Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Andrews, Jane M., Baidoo, Leonard, Balschun, Tobias, Bampton, Peter A., Bitton, Alain, Boucher, Gabrielle, Brand, Stephan, Büning, Carsten, Cohain, Ariella, Cichon, Sven, D'Amato, Mauro, De Jong, Dirk, Devaney, Kathy L., Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Ferguson, Lynnette R., Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hedl, Matija, Xinli, Hu, Karlsen, Tom H., Kupcinskas, Limas, Kugathasan, Subra, Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lees, Charlie W., Louis, Edouard, Mahy, Gillian, Mansfield, John, Morgan, Angharad R., Mowat, Craig, Newman, William, Palmieri, Orazio, Ponsioen, Cyriel Y., Potocnik, Uros, Prescott, Natalie J., Regueiro, Miguel, Rotter, Jerome I., Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schreiber, Stefan, Simms, Lisa A., Sventoraityte, Jurgita, Targan, Stephan R., Taylor, Kent D., Tremelling, Mark, Verspaget, Hein W., De Vos, Martine, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Xavier, Ramnik J., Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhao, Hongyu, Silverberg, Mark S., Annese, Vito, Hakonarson, Hakon, Brant, Steven R., Radford Smith, Graham, Mathew, Christopher G., Rioux, John D., Schadt, Eric E., Daly, Mark J., Franke, Andre, Parkes, Miles, Vermeire, Severine, Barrett, Jeffrey C., Cho, Judy H., Barclay, M, Peyrin Biroulet, L, Chamaillard, M, Colombel, Jf, Cottone, M, Croft, A, D'Incà, R, Halfvarson J, Hanigan K, Henderson, P, Hugot, Jp, Karban, A, Kennedy, Na, Khan, Ma, Lémann, M, Levine, A, Massey, D, Milla, M, Montgomery, Gw, Ng, Sm, Oikonomou, I, Peeters, H, Proctor, Dd, Rahier, Jf, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, Laura, Taylor, Km, Törkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, Mh, Zhang, H, Zhang, W, Andrews, Jm, Bampton, Pa, Florin, Th, Gearry, R, Krishnaprasad, K, Lawrance, Ic, Mahy, G, Radford Smith, G, Roberts, Rl, Simms, La, Amininijad, L, Cleynen, I, Dewit, O, Franchimont, D, Georges, M, Laukens, D, Theatre, E, Vermeire, S, Aumais, G, Baidoo, L, Barrie AM 3rd, Beck, K, Bernard, Ej, Binion, Dg, Bitton, A, Brant, Sr, Cho, Jh, Cohen, A, Croitoru, K, Daly, Mj, Datta, Lw, Deslandres, C, Duerr, Rh, Dutridge, D, Ferguson, J, Fultz, J, Goyette, P, Greenberg, Gr, Haritunians, T, Jobin, G, Katz, S, Lahaie, Rg, Mcgovern, Dp, Nelson, L, Ning, K, Paré, P, Regueiro, Md, Rioux, Jd, Ruggiero, E, Schumm, L, Schwartz, M, Scott, R, Sharma, Y, Silverberg, Ms, Spears, D, Steinhart, A, Stempak, Jm, Swoger, Jm, Tsagarelis, C, Zhang, C, Zhao, H, Aerts, J, Ahmad, T, Arbury, H, Attwood, A, Auton, A, Ball, Sg, Balmforth, Aj, Barnes, C, Barrett, Jc, Barroso, I, Barton, A, Bennett, Aj, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, Oj, Braund, Ps, Bredin, F, Breen, G, Brown, Mj, Bruce, In, Bull, J, Burren, Os, Burton, J, Byrnes, J, Caesar, S, Cardin, N, Clee, Cm, Coffey, Aj, Connell, Jm, Conrad, Df, Cooper, Jd, Dominiczak, Af, Downes, K, Drummond, He, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, Dm, Evans, G, Eyre, S, Farmer, A, Ferrier, In, Flynn, E, Forbes, A, Forty, L, Franklyn, Ja, Frayling, Tm, Freathy, Rm, Giannoulatou, E, Gibbs, P, Gilbert, P, Gordon Smith, K, Gray, E, Green, E, Groves, Cj, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, Ga, Hocking, L, Holmes, C, Howard, E, Howard, P, Howson, Jm, Hughes, D, Hunt, S, Isaacs, Jd, Jain, M, Jewell, Dp, Johnson, T, Jolley, Jd, Jones, Ir, Jones, La, Kirov, G, Langford, Cf, Lango Allen, H, Lathrop, Gm, Lee, J, Lee, Kl, Lees, C, Lewis, K, Lindgren, Cm, Maisuria Armer, M, Maller, J, Mansfield, J, Marchini, Jl, Martin, P, Massey, Dc, Mcardle, Wl, Mcguffin, P, Mclay, Ke, Mcvean, G, Mentzer, A, Mimmack, Ml, Morgan, Ae, Morris, Ap, Mowat, C, Munroe, Pb, Myers, S, Newman, W, Nimmo, Er, O'Donovan, Mc, Onipinla, A, Ovington, Nr, Owen, Mj, Palin, K, Palotie, A, Parnell, K, Pearson, R, Pernet, D, Perry, Jr, Phillips, A, Plagnol, V, Prescott, Nj, Prokopenko, I, Quail, Ma, Rafelt, S, Rayner, Nw, Reid, Dm, Renwick, A, Ring, Sm, Robertson, N, Robson, S, Russell, E, St Clair, D, Sambrook, Jg, Sanderson, Jd, Sawcer, Sj, Schuilenburg, H, Scott, Ce, Seal, S, Shaw Hawkins, S, Shields, Bm, Simmonds, Mj, Smyth, Dj, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, He, Stirrups, K, Stone, Ma, Strachan, Dp, Su, Z, Symmons, Dp, Thompson, Jr, Thomson, W, Tobin, Md, Travers, Me, Turnbull, C, Vukcevic, D, Wain, Lv, Walker, M, Walker, Nm, Wallace, C, Warren Perry, M, Watkins, Na, Webster, J, Weedon, Mn, Wilson, Ag, Woodburn, M, Wordsworth, Bp, Yau, C, Young, Ah, Zeggini, E, Brown, Ma, Burton, Pr, Caulfield, Mj, Compston, A, Farrall, M, Gough, Sc, Hall, As, Hattersley, At, Hill, Av, Mathew, Cg, Pembrey, M, Satsangi, J, Stratton, Mr, Worthington, J, Hurles, Me, Duncanson, A, Ouwehand, Wh, Parkes, M, Rahman, N, Todd, Ja, Samani, Nj, Kwiatkowski, Dp, Mccarthy, Mi, Craddock, N, Deloukas, P, Donnelly, P, Blackwell, Jm, Bramon, E, Casas, Jp, Corvin, A, Jankowski, J, Markus, Hs, Palmer, Cn, Plomin, R, Rautanen, A, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cc, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Pirinen, M, Strange, A, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Genome-wide association study, Disease, SUSCEPTIBILITY, Inflammatory bowel disease, NUMBER, 0302 clinical medicine, Crohn Disease, NETWORK, Genetics, 0303 health sciences, Multidisciplinary, Genomics, Ulcerative colitis, 3. Good health, Colitis, Ulcerative, Genetic Predisposition to Disease, Genome, Human, Haplotypes, Humans, Inflammatory Bowel Diseases, Mycobacterium, Mycobacterium Infections, Mycobacterium tuberculosis, Phenotype, Polymorphism, Single Nucleotide, Reproducibility of Results, Genome-Wide Association Study, Host-Pathogen Interactions, IRGM, Medical genetics, 030211 gastroenterology & hepatology, EXPRESSION, medicine.medical_specialty, Immunology, Biology, Molecular gastro-enterology and hepatology Pathogenesis and modulation of inflammation [IGMD 2], TUBERCULOSIS, 03 medical and health sciences, Medical research, medicine, Allele, METAANALYSIS, 030304 developmental biology, HYPER-IGE SYNDROME, MUTATIONS, medicine.disease, RISK LOCI, Genetic architecture, digestive system diseases
Abstract

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Published
2012

26. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

Author

Liu, Jimmy Z, Hov, Johannes Roksund, Folseraas, Trine, Ellinghaus, Eva, Rushbrook, Simon M, Doncheva, Nadezhda T, Andreassen, Ole A, Weersma, Rinse K, Weismüller, Tobias J, Eksteen, Bertus, Invernizzi, Pietro, Hirschfield, Gideon M, Gotthardt, Daniel Nils, Pares, Albert, Ellinghaus, David, Shah, Tejas, Juran, Brian D, Milkiewicz, Piotr, Rust, Christian, Schramm, Christoph, Müller, Tobias, Srivastava, Brijesh, Dalekos, Georgios, Nöthen, Markus M, Herms, Stefan, Winkelmann, Juliane, Mitrovic, Mitja, Braun, Felix, Ponsioen, Cyriel Y, Croucher, Peter JP, Sterneck, Martina, Teufel, Andreas, Mason, Andrew L, Saarela, Janna, Leppa, Virpi, Dorfman, Ruslan, Alvaro, Domenico, Floreani, Annarosa, Onengut-Gumuscu, Suna, Rich, Stephen S, Thompson, Wesley K, Schork, Andrew J, Næss, Sigrid, Thomsen, Ingo, Mayr, Gabriele, König, Inke R, Hveem, Kristian, Cleynen, Isabelle, Gutierrez-Achury, Javier, Ricaño-Ponce, Isis, Van Heel, David, Björnsson, Einar, Sandford, Richard N, Durie, Peter R, Melum, Espen, Vatn, Morten H, Silverberg, Mark S, Duerr, Richard H, Padyukov, Leonid, Brand, Stephan, Sans, Miquel, Annese, Vito, Achkar, Jean-Paul, Boberg, Kirsten Muri, Marschall, Hanns-Ulrich, Chazouillères, Olivier, Bowlus, Christopher L, Wijmenga, Cisca, Schrumpf, Erik, Vermeire, Severine, Albrecht, Mario, UK-PSCSC Consortium, Rioux, John D, Alexander, Graeme, Bergquist, Annika, Cho, Judy, Schreiber, Stefan, Manns, Michael P, Färkkilä, Martti, Dale, Anders M, Chapman, Roger W, Lazaridis, Konstantinos N, International PSC Study Group, Franke, Andre, Anderson, Carl A, Karlsen, Tom H, and International IBD Genetics Consortium

Subjects
endocrine system diseases, Genotyping Techniques, digestive, oral, and skin physiology, Cholangitis, Sclerosing, Genetic Pleiotropy, digestive system, Polymorphism, Single Nucleotide, digestive system diseases, Linkage Disequilibrium, 3. Good health, Gene Frequency, Genetic Loci, Risk Factors, Case-Control Studies, Humans, Genome-Wide Association Study, Oligonucleotide Array Sequence Analysis
Abstract

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

27. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Author

Benyamin, Beben, Esko, Tonu, Ried, Janina S, Radhakrishnan, Aparna, Vermeulen, Sita H, Traglia, Michela, Gögele, Martin, Anderson, Denise, Broer, Linda, Podmore, Clara, Luan, Jian'an, Kutalik, Zoltan, Sanna, Serena, Van Der Meer, Peter, Tanaka, Toshiko, Wang, Fudi, Westra, Harm-Jan, Franke, Lude, Mihailov, Evelin, Milani, Lili, Hälldin, Jonas, Winkelmann, Juliane, Meitinger, Thomas, Thiery, Joachim, Peters, Annette, Waldenberger, Melanie, Rendon, Augusto, Jolley, Jennifer, Sambrook, Jennifer, Kiemeney, Lambertus A, Sweep, Fred C, Sala, Cinzia F, Schwienbacher, Christine, Pichler, Irene, Hui, Jennie, Demirkan, Ayse, Isaacs, Aaron, Amin, Najaf, Steri, Maristella, Waeber, Gérard, Verweij, Niek, Powell, Joseph E, Nyholt, Dale R, Heath, Andrew C, Madden, Pamela AF, Visscher, Peter M, Wright, Margaret J, Montgomery, Grant W, Martin, Nicholas G, Hernandez, Dena, Bandinelli, Stefania, Van Der Harst, Pim, Uda, Manuela, Vollenweider, Peter, Scott, Robert A, Langenberg, Claudia, Wareham, Nicholas J, InterAct Consortium, Van Duijn, Cornelia, Beilby, John, Pramstaller, Peter P, Hicks, Andrew A, Ouwehand, Willem H, Oexle, Konrad, Gieger, Christian, Metspalu, Andres, Camaschella, Clara, Toniolo, Daniela, Swinkels, Dorine W, and Whitfield, John B

Subjects
Adult, Iron, Transferrin, Reproducibility of Results, Lipids, Polymorphism, Single Nucleotide, 3. Good health, Phenotype, Gene Expression Regulation, Genetic Loci, Risk Factors, Ferritins, Homeostasis, Humans, Genetic Predisposition to Disease, Hemochromatosis, Chromosomes, Human, Pair 7, Genetic Association Studies
Abstract

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P

28. Common variants in P2RY11 are associated with narcolepsy (vol 43, pg 66, 2011)

Author

Kornum, Birgitte R., Kawashima, Minae, Faraco, Juliette, Lin, Ling, Rico, Thomas J., Hesselson, Stephanie, Axtell, Robert C., Kuipers, Hedwich, Weiner, Karin, Hamacher, Alexandra, Kassack, Matthias U., Han, Fang, Knudsen, Stine, Li, Jing, Dong, Xiaosong, Winkelmann, Juliane, Plazzi, Giuseppe, Sona Nevsimalova, Hong, Seung-Chul, Honda, Yutaka, Honda, Makoto, Hoegl, Birgit, Ton, Thanh G. N., Montplaisir, Jacques, Bourgin, Patrice, Kemlink, David, Huang, Yu-Shu, Warby, Simon, Einen, Mali, Eshragh, Jasmin L., Miyagawa, Taku, Desautels, Alex, Ruppert, Elisabeth, Hesla, Per Egil, Poli, Francesca, Pizza, Fabio, Frauscher, Birgit, Jeong, Jong-Hyun, Lee, Sung-Pil, Strohl, Kingman P., Longstreth, William T., Kvale, Mark, Dobrovolna, Marie, Ohayon, Maurice M., Nepom, Gerald T., Wichmann, H-Erich, Rouleau, Guy A., Gieger, Christian, Levinson, Douglas F., Gejman, Pablo V., Meitinger, Thomas, Peppard, Paul, Young, Terry, Jennum, Poul, Steinman, Lawrence, Tokunaga, Katsushi, Kwok, Pui-Yan, Risch, Neil, Hallmayer, Joachim, and Mignot, Emmanuel

29. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

Author

Schormair, Barbara, Zhao, Chen, Bell, Steven, Tilch, Erik, Salminen, Aaro V, Pütz, Benno, Dauvilliers, Yves, Stefani, Ambra, Högl, Birgit, Poewe, Werner, Kemlink, David, Sonka, Karel, Bachmann, Cornelius G, Paulus, Walter, Trenkwalder, Claudia, Oertel, Wolfgang H, Hornyak, Magdolna, Teder-Laving, Maris, Metspalu, Andres, Hadjigeorgiou, Georgios M, Polo, Olli, Fietze, Ingo, Ross, Owen A, Wszolek, Zbigniew, Butterworth, Adam S, Soranzo, Nicole, Ouwehand, Willem H, Roberts, David J, Danesh, John, Allen, Richard P, Earley, Christopher J, Ondo, William G, Xiong, Lan, Montplaisir, Jacques, Gan-Or, Ziv, Perola, Markus, Vodicka, Pavel, Dina, Christian, Franke, Andre, Tittmann, Lukas, Stewart, Alexandre FR, Shah, Svati H, Gieger, Christian, Peters, Annette, Rouleau, Guy A, Berger, Klaus, Oexle, Konrad, Di Angelantonio, Emanuele, Hinds, David A, Müller-Myhsok, Bertram, Winkelmann, Juliane, 23andMe Research Team, and DESIR Study Group

Subjects
DNA-Binding Proteins, Restless Legs Syndrome, European Continental Ancestry Group, Humans, Genetic Predisposition to Disease, Nerve Tissue Proteins, Semaphorins, GPI-Linked Proteins, 3. Good health, Genome-Wide Association Study, Transcription Factors
Abstract

BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10(-8)) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

31. A Novel Genetic Basis For Systemic Vasculitis: Polyarteritis Nodosa Caused By Recessive Mutations In An Immune-Related Gene

Author

Segel, Reeval, Elkan-Navon, Pnina, Pierce, Sarah B., Walsh, Tom, Barash, Judith, Padeh, Shay, Zlotogorski, Avraham, Yackov Berkun, Voth, Isabel, Hashkes, Philip, Harel, Liora, Ling, Eduard, Yalcinkaya, Fatos, Kasapcopur, Ozgur, Renbaum, Paul F., Weinberg-Shukron, Ariella, Schormair, Barbara, Shohat, Mordechai, Rubinow, Alan A., Pras, Elon, Winkelmann, Juliane, Tekin, Mustafa, Anikster, Yair, King, Mary-Claire, and Levy-Lahad, Ephrat

32. Genetics of Restless Legs Syndrome

Author

Tilch, Erik, Fries, Hans-Rudolf (Prof. Dr.), Winkelmann, Juliane (Prof. Dr.), and Müller-Myhsok, Bertram (Prof. Dr.)

Subjects
Biowissenschaften, Biologie, ddc:570
Abstract

The genetically complex restless legs syndrome (RLS) was tested for associations with genes using rare variant ExomeChip genotypes of 9,192 cases/controls. Candidate genes were sequenced together with candidate genes from a meta-GWAS using MIPseq in 1,456 cases/controls. A list of potential RLS genes was obtained. Furthermore, 843 individuals from 79 RLS families were genotyped/imputed for RLS risk SNPs. They were associated with RLS in 15 families and explained 17% to 100% of the phenotypic variance. « Übersetzte Kurzfassung: Das komplex-genetische Restless Legs Syndrom (RLS) wurde unter der Verwendung seltener Varianten aus dem ExomeChip von 9.192 Fällen/Kontrollen auf Assoziationen mit Genen getestet. Die resultierenden Kandidatengene und weitere Kandidatengene aus einer Meta-GWAS wurden mittels MIPseq in 1.456 Fällen/Kontrollen sequenziert. Eine Liste potentieller RLS Gene wurde erhalten. Auch wurden bekannte RLS-Risiko-SNPs in 843 Personen aus 79 RLS-Familien typisiert. Die SNPs waren mit RLS in 15 Familien assoziiert und erklärten 17 % bis 100 % der phänotypischen Varianz.

Published
2018

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