DOCSLIB.ORG

A Rare Truncating Mutation in ADH1C (G78stop) Shows Significant Association with Parkinson Disease in a Large International Sample

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Rare Truncating Mutation in ADH1C (G78stop) Shows Significant Association with Parkinson Disease in a Large International Sample ORIGINAL CONTRIBUTION A Rare Truncating Mutation in ADH1C (G78Stop) Shows Significant Association With Parkinson Disease in a Large International Sample Silvia Buervenich, PhD; Andrea Carmine, PhD; Dagmar Galter, PhD; Haydeh N. Shahabi, MS; Bo Johnels, MD, PhD; Björn Holmberg, MD, PhD; Jarl Ahlberg, MD; Hans Nissbrandt, MD, PhD; Johanna Eerola, MD; Olli Hellström, MD; Pentti J. Tienari, MD, PhD; Tohru Matsuura, MD; Tetsuo Ashizawa, MD; Ullrich Wüllner, MD; Thomas Klockgether, MD; Alexander Zimprich, MD; Thomas Gasser, MD; Melissa Hanson, MS; Shamaila Waseem, MD; Andrew Singleton, PhD; Francis J. McMahon, MD; Maria Anvret, PhD; Olof Sydow, MD, PhD; Lars Olson, PhD Background: Alcohol dehydrogenases (ADHs) may be 1076 PD patients of European ancestry and 940 involved in the pathogenesis of neurodegenerative dis- matched controls. orders because of their multiple roles in detoxification pathways and retinoic acid synthesis. In a previous Results: The previously identified association with an ADH study, significant association of an ADH class IV allele class IV allele remained significant (PϽ.02) in the ex- with Parkinson disease (PD) was found in a Swedish tended Swedish study. Furthermore, in the international sample. collaboration, the G78stop mutation in ADH1C was found in 22 (2.0%) of the PD patients but only in 6 controls (0.6%). ␹2 Patients: The previously associated single-nucleotide This association was statistically significant ( 1=7.5; 2-sided polymorphism plus 12 further polymorphisms in the P=.007; odds ratio, 3.25 [95% confidence interval, 1.31- ADH cluster on human chromosome 4q23 were 8.05]). In addition, the G78stop mutation was identified screened for association in an extension of the original in 4 (10.0%) of 40 Caucasian index cases with PD with sample that now included 123 Swedish PD patients and mainly hereditary forms of the disorder. 127 geographically matched control subjects. A rare nonsense single-nucleotide polymorphism in ADH1C Conclusion: Findings presented herein provide further (G78stop, rs283413) was identified in 3 of these evidence for mutations in genes encoding ADHs as ge- patients but in no controls. To obtain sufficient power netic risk factors for PD. to detect a possible association of this rare variant with disease, we screened a large international sample of Arch Neurol. 2005;62:74-78 HE ETIOLOGY OF PARKIN- rahydroisoquinolines similar to MPTP son disease (PD) remains (N-methyl-4-phenyl-1,2,3,6-tetrahy- largely a mystery despite dropyridine).6 In addition, proper devel- considerable research ef- opment and maintenance of the dopamin- forts in the fields of epide- ergic system may be strongly dependent on miology, genetics, biochemistry, and cel- the supply of retinoic acid,7 which needs T1 8 lular biology. Neurodegeneration in PD is to be synthesized from retinol. most prominent in the dopaminergic cell Alcohol dehydrogenase (ADH) en- population,2 but is by no means confined zymes of classes I and IV are mainly ex- to this anatomical site,3 suggesting a more pressed in the lining of the digestive tract widespread metabolic deficiency and/or and in the liver.9 They are thought to play toxic event in the pathogenesis of the dis- important roles in the metabolism of etha- order. Epidemiological data suggest that en- nol and in the synthesis of retinoic acid, and vironmental factors are likely to play a role may also be important in the detoxifica- in PD pathogenesis,4 although the exact na- tion of reactive substances such as 4-hy- ture of such agents remains to be identi- droxynonenal. The dehydrogenases may, fied. Among candidate environmental risk therefore, constitute a first line of defense substances for PD are substances leading in the gastrointestinal tract against exog- to enhanced oxidative stress and lipid per- enous toxic agents, and genetic defects in oxidation products, such as reactive alde- these enzymes may lead to increased up- hydes.5 Mesencephalic dopamine neu- take of potentially harmful substances that rons may be especially vulnerable to reactive may eventually reach the dopamine sys- Author Affiliations are listed at substances because aldehydes may react tem of the brain. Proper function of these the end of this article. with dopamine in vivo, forming toxic tet- enzymes may also be required during pe- (REPRINTED) ARCH NEUROL / VOL 62, JAN 2005 WWW.ARCHNEUROL.COM 74 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 riods of reduced access to retinol or, conversely, during dietary overload of retinoids.10 Studying genetic variation Table 1. SNPs Across the ADH Cluster in genes encoding ADH enzymes may, thus, offer links be- at 4q23 Selected for This Study tween nature and nurture in the pathogenesis of the dif- Location and ferent manifestations of PD. Location Polymorphism, Characterization of In a sample of Swedish patients, association with PD of SNP Reference Allele 1/Allele 2 the Sequence Change was previously identified for a haplotype at the ADH4 gene ADH1B (also known as ADH7; the present study uses the more I rs1041969 C/A Exon 3, N57K 11 recent class-based nomenclature ), encoding a class IV II rs17033 T/C Exon 9, UTR ADH, µ or ␴ subunit.12 This finding, however, could not ADH1C be reproduced in a US sample of unrelated PD pa- I rs283413 G/T Exon 3, G78Stop tients.13 We selected the previously associated single- II rs1693482 A/G Exon 5, Q272R nucleotide polymorphism (SNP) plus 12 further SNPs III rs1042758 G/A Exon 7, V350I 14 ADH3 from the literature and the public SNP database. These I Reference 14 C/T Promoter, C+9/T+9 SNPs are located in 2 class I genes, class III ADH, and II Reference 14 G/A Promoter, G−79/A−79 class IV ADH (Table 1). One of the nucleotide varia- III Reference 14 GG/AA Exon 1, silent, GG−197, tions (rs283413) led to a predicted early truncation of GG−196/AA−197, AA−196 the protein chain at residue 78 of the ADH1C protein se- IV rs13832 T/G Exon 9, UTR quence (Figure). Nonsense mutations have been shown ADH4 I rs1573496 and G/C Exon 3, G92A, P5 to be 9 times more likely to lead to a phenotype than mu- reference 12 15 tations leading to amino acid substitutions, and de- II Reference 12 A/G Promoter, P1 serve special attention in sequence-based association stud- III Reference 12 T/C Promoter, P2 ies such as this one. Possible association of this variant IV rs971074 and G/A Exon 6, silent, P7 with PD was, therefore, tested in a further international reference 12 extension of the study by obtaining DNA from 1076 PD Abbreviations: ADH, alcohol dehydrogenase; SNP, single-nucleotide patients and 940 control subjects. polymorphism; UTR, untranslated region. METHODS set of the material described herein, no significant asso- Approval for this study was obtained from the local ethical com- ciation of the investigated SNPs with PD was found. mittees by each recruiting site, and samples were drawn after A SNP retrieved from a public database, rs283413, lead- informed consent. Seven collections of samples from PD pa- tients and geographically matched controls were combined for ing to an early truncation of the ADH1C protein chain, was case-control analysis (Table 2 provides the diagnostic crite- identified in 3 patients, but was absent from control samples. ria and demographic details). To establish case-control DNA We screened for the presence or absence of this ADH1C material for the London Brain Bank collection, tissue samples nonsense variant in a large collaborative sample of 1076 were supplied by the Queen Square Brain Bank for Neurologi- PD patients of European ancestry and 940 matched con- cal Disorders, London, England. DNA was extracted from tis- trols. There was a significant association with PD in the total ␹ 2 sue blocks using a standard kit (Qiagen; VWR International AB, sample (Table 4)( 1=7.5; 2-sided P=.007; odds ratio, Stockholm). DNA samples from 129 unrelated CEPH (Centre 3.25 [95% confidence interval, 1.31-8.05]). The ADH1C d’Etude du Polymorphisme Humain) founders from the French nonsense mutation was also found in an additional 4 of 40 and Utah pedigrees were purchased from Coriell Cell Reposi- tested Caucasian patients with PD, 3 having a strong fam- tories, Camden, Pa. An eighth collection sample (not in- cluded in the case-control study because of variable ascertain- ily history of the disorder and 1 being a sporadic case. No ment and lack of controls for this sample) contained DNA from DNA was available from further affected or unaffected fam- 40 Caucasian PD patients with mainly hereditary types of PD. ily members of these mutation carriers. Genotyping was performed by pyrosequencing, as described Previous studies performed by other investigators have in detail elsewhere.18 Sequences of primers, magnesium con- suggested large regions of linkage disequilibrium (LD) centrations, and nucleotide dispensation orders are available within the ADH cluster.19 Herein, we studied LD in the from us on request. The presence of the ADH1C nonsense mu- Swedish case-control material for the 13 SNPs listed in tation was confirmed by automated capillary sequencing or re- Table 1. The results indicate that there is extensive LD within striction fragment length polymorphism analysis using the BsaXI the ADH cluster in the Swedish population (data available ␹2 restriction enzyme. Tests were performed for association test- from us on request). In addition, to determine how far LD ing of all variants identified. P values and significance values given in the text are nominal values without correction for mul- extended between the identified truncating mutation in tiple testing. ADH1C and other SNPs within the cluster or at its border, we studied 40 SNPs in a 4.8-megabase region around the ADH gene cluster in 3 Swedish and 2 English mutation car- RESULTS riers.
Load more

Recommended publications
  • Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’S Biological Network Based on Systematic Pharmacology
    ORIGINAL RESEARCH published: 25 June 2021 doi: 10.3389/fphar.2021.601846 Exploring the Regulatory Mechanism of Hedysarum Multijugum Maxim.-Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’s Biological Network Based on Systematic Pharmacology Kailin Yang 1†, Liuting Zeng 1†, Anqi Ge 2†, Yi Chen 1†, Shanshan Wang 1†, Xiaofei Zhu 1,3† and Jinwen Ge 1,4* Edited by: 1 Takashi Sato, Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of 2 Tokyo University of Pharmacy and Life Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China, Galactophore Department, The First 3 Sciences, Japan Hospital of Hunan University of Chinese Medicine, Changsha, China, School of Graduate, Central South University, Changsha, China, 4Shaoyang University, Shaoyang, China Reviewed by: Hui Zhao, Capital Medical University, China Background: Clinical research found that Hedysarum Multijugum Maxim.-Chuanxiong Maria Luisa Del Moral, fi University of Jaén, Spain Rhizoma Compound (HCC) has de nite curative effect on cerebral ischemic diseases, *Correspondence: such as ischemic stroke and cerebral ischemia-reperfusion injury (CIR). However, its Jinwen Ge mechanism for treating cerebral ischemia is still not fully explained. [email protected] †These authors share first authorship Methods: The traditional Chinese medicine related database were utilized to obtain the components of HCC. The Pharmmapper were used to predict HCC’s potential targets. Specialty section: The CIR genes were obtained from Genecards and OMIM and the protein-protein This article was submitted to interaction (PPI) data of HCC’s targets and IS genes were obtained from String Ethnopharmacology, a section of the journal database.
    [Show full text]
  • The Genetics of Alcohol Dependence: Advancing Towards Systems-Based Approaches
    Drug and Alcohol Dependence 125 (2012) 179–191 Contents lists available at SciVerse ScienceDirect Drug and Alcohol Dependence jo urnal homepage: www.elsevier.com/locate/drugalcdep Review The genetics of alcohol dependence: Advancing towards systems-based approaches a,b,c,∗ a,b,c a,d e f g a,b R.H.C. Palmer , J.E. McGeary , S. Francazio , B.J. Raphael , A.D. Lander , A.C. Heath , V.S. Knopik a Division of Behavioral Genetics, Department of Psychiatry at Rhode Island Hospital, United States b Department of Psychiatry and Human Behavior at the Warren Alpert Medical School of Brown University, United States c Department of Veterans Affairs, Providence, RI, United States d Providence College, Providence, United States e Department of Computer Science, and Center for Computational Molecular Biology, Brown University, United States f Department of Developmental and Cell Biology, University of California, Irvine, United States g Department of Psychiatry, Washington University School of Medicine, St. Louis, United States a r t i c l e i n f o a b s t r a c t Article history: Background: Personalized treatment for psychopathologies, in particular alcoholism, is highly dependent Received 7 February 2012 upon our ability to identify patterns of genetic and environmental effects that influence a person’s risk. Received in revised form 9 July 2012 Unfortunately, array-based whole genome investigations into heritable factors that explain why one Accepted 10 July 2012 person becomes dependent upon alcohol and another does not, have indicated that alcohol’s genetic Available online 31 July 2012 architecture is highly complex.
    [Show full text]
  • Computational Exploration of the Medium-Chain Dehydrogenase / Reductase Superfamily
    From the Department of Medical Biochemistry and Biophysics Karolinska Institutet, Stockholm, Sweden COMPUTATIONAL EXPLORATION OF THE MEDIUM-CHAIN DEHYDROGENASE / REDUCTASE SUPERFAMILY Linus J. Östberg Stockholm 2017 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by E-Print AB 2017 ©Linus J. Östberg, 2017 ISBN 978-91-7676-650-7 COMPUTATIONAL EXPLORATION OF THE MEDIUM-CHAIN DEHYDROGENASE / REDUCTASE SUPERFAMILY THESIS FOR DOCTORAL DEGREE (Ph.D.) By Linus J. Östberg Principal Supervisor: Opponent: Prof. Jan-Olov Höög Prof. Jaume Farrés Karolinska Institutet Autonomous University of Barcelona Department of Medical Biochemistry and Department of Biochemistry and Biophysics Molecular Biology Co-supervisor: Examination Board: Prof. Bengt Persson Prof. Erik Lindahl Uppsala University Stockholm University Department of Cell and Molecular Biology Department of Biochemistry and Biophysics Assoc. Prof. Tanja Slotte Stockholm University Department of Ecology, Environment and Plant Sciences Prof. Elias Arnér Karolinska Institutet Department of Medical Biochemistry and Biophysics ABSTRACT The medium-chain dehydrogenase/reductase (MDR) superfamily is a protein family with more than 170,000 members across all phylogenetic branches. In humans there are 18 repre- sentatives. The entire MDR superfamily contains many protein families such as alcohol dehy- drogenase, which in mammals is in turn divided into six classes, class I–VI (ADH1–6). Most MDRs have enzymatical functions, catalysing the conversion of alcohols to aldehyde/ketones and vice versa, but the function of some members is still unknown. In the first project, a methodology for identifying and automating the classification of mammalian ADHs was developed using BLAST for identification and class-specific hidden Markov models were generated for identification.
    [Show full text]
  • ARTICLE Evidence of Positive Selection on a Class I ADH Locus
    ARTICLE Evidence of Positive Selection on a Class I ADH Locus Yi Han,* Sheng Gu,* Hiroki Oota,† Michael V. Osier,‡ Andrew J. Pakstis, William C. Speed, Judith R. Kidd, and Kenneth K. Kidd The alcohol dehydrogenase (ADH) family of enzymes catalyzes the reversible oxidation of alcohol to acetaldehyde. Seven ADH genes exist in a segment of ∼370 kb on 4q21. Products of the three class I ADH genes that share 95% sequence identity are believed to play the major role in the first step of ethanol metabolism. Because the common belief that selection has operated at the ADH1B*47His allele in East Asian populations lacks direct biological or statistical evidence, we used genomic data to test the hypothesis. Data consisted of 54 single-nucleotide polymorphisms (SNPs) across the ADH clusters in a global sampling of 42 populations. Both the Fst statistic and the long-range haplotype (LRH) test provided positive evidence of selection in several East Asian populations. The ADH1B Arg47His functional polymorphism has the highest Fst of the 54 SNPs in the ADH cluster, and it is significantly above the mean Fst of 382 presumably neutral sites tested on the same 42 population samples. The LRH test that uses cores including that site and extending on both sides also gives significant evidence of positive selection in some East Asian populations for a specific haplotype carrying the ADH1B*47His allele. Interestingly, this haplotype is present at a high frequency in only some East Asian populations, whereas the specific allele also exists in other East Asian populations and in the Near East and Europe but does not show evidence of selection with use of the LRH test.
    [Show full text]
  • For Poststroke Depression Based on Network Pharmacology and Molecular Docking
    Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2021, Article ID 2126967, 14 pages https://doi.org/10.1155/2021/2126967 Research Article Exploring the Mechanism of Action of Herbal Medicine (Gan-Mai-Da-Zao Decoction) for Poststroke Depression Based on Network Pharmacology and Molecular Docking Zhicong Ding ,1 Fangfang Xu,1 Qidi Sun,2 Bin Li,1 Nengxing Liang,1 Junwei Chen,1 and Shangzhen Yu 1,3 1Jinan University, Guangzhou 510632, China 2Yangzhou University, Yangzhou 225009, China 3Wuyi Hospital of Traditional Chinese Medicine, Jiangmen 529000, China Correspondence should be addressed to Shangzhen Yu; [email protected] Received 19 May 2021; Accepted 14 August 2021; Published 23 August 2021 Academic Editor: Ghulam Ashraf Copyright © 2021 Zhicong Ding et al. -is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Poststroke depression (PSD) is the most common and serious neuropsychiatric complication occurring after ce- rebrovascular accidents, seriously endangering human health while also imposing a heavy burden on society. Nevertheless, it is difficult to control disease progression. Gan-Mai-Da-Zao Decoction (GMDZD) is effective for PSD, but its mechanism of action in PSD is unknown. In this study, we explored the mechanism of action of GMDZD in PSD treatment using network pharmacology and molecular docking. Material and methods. We obtained the active components of all drugs and their targets from the public database TCMSP and published articles. -en, we collected PSD-related targets from the GeneCards and OMIM databases.
    [Show full text]
  • Aldh2, Adh1b, and Adh1c Genotypes in Asians: A
    FOCUS ON SPECIAL POPULATIONS ALDH2, ADH1B, AND ADH1C GENOTYPES data from over 4,500 alcohol-dependent and control sub­ IN ASIANS: A LITERATURE REVIEW jects collected between 1979 and 2004 found possession of one variant ALDH2*2 allele was associated with a five­ fold reduction in alcohol is dependence and possession of Mimy Y. Eng, Ph.D.; Susan E. Luczak, Ph.D.; two ALDH2*2 alleles was associated with a nine-fold and Tamara L. Wall, Ph.D. reduction (Luczak et al. 2006).3 In Asians with no ALDH2*2 alleles, possession of one variant ADH1B*2 Variants of three genes encoding alcohol-metabolizing allele was associated with a four-fold reduction in alcohol enzymes, the aldehyde dehydrogenase gene ALDH2 and the dependence and possession of two ADH1B*2 alleles was alcohol dehydrogenase genes ADH1B and ADH1C, have associated with a five-fold reduction (Luczak et al. 2006). been associated with reduced rates of alcohol dependence. ADH1C*1 also has been related to protection against The genotype prevalence of these genes varies in general alcohol dependence, but this association has been attribut­ ed to the gene being in close proximity to the samples of different Asian ethnic groups. The ALDH2*2 ADH1C ADH1B gene on the chromosome so that the genotypes allele appears to be most prevalent in Chinese-American, are correlated (Osier et al. 1999). Han Chinese and Taiwanese, Japanese, and Korean samples. Determining how frequently certain genotypes occur Much lower rates have been reported in Thais, Filipinos, in different populations is useful for behavioral genetics Indians, and Chinese and Taiwanese aborigines.
    [Show full text]
  • Research on the Mechanism of Wuwei Yuganzi San in the Treatment of Coronary Heart Disease Based on Network Pharmacology
    Research on the Mechanism of Wuwei Yuganzi San in the Treatment of Coronary Heart Disease Based on Network Pharmacology Qunhui Zhang Qinghai University Medical College https://orcid.org/0000-0002-4021-5669 Yimei Li Xizang Minzu University Yang Guo Qinghai University Medical College Qiqin Lu Qinghai University Guoying Zhang Qinghai University Jing Ma Qinghai University Dejun Zhang ( [email protected] ) Medical College of Qinghai University https://orcid.org/0000-0002-1436-1910 Research Keywords: Network Pharmacology, CHD, WYS, Targets, Mechanism Posted Date: April 1st, 2021 DOI: https://doi.org/10.21203/rs.3.rs-360519/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/20 Abstract Background: Coronary heart disease (CHD) is a chronic cardiovascular disease across the world, which poses numerous threats to mankind. Wuwei Yuganzi San (WYS) is a famous traditional Tibetan medicine prescription. It has been conrmed effective in the treatment of CHD, but its specic mechanism remains still unclear. Objective: To elucidate the main pharmacological action of WYS in treating CHD and investigate the underlying multiple mechanisms of its multi-ingredient-multi-target by network pharmacology. Methods: Firstly, active ingredients of WYS and connected targets of ve herbs were retrieved by using traditional Chinese medicine systems pharmacology (TCMSP) and screening literature. Then, genome explanation databases (OMIM and GeneCards) were used to acquire targets related to CHD. The protein- protein interaction (PPI) network was built using the mutual targets ltering genes through protein interaction. Next, a network diagram could be established with the help of Cytoscape 3.8.2.
    [Show full text]
  • Comparative Genomics Reveals Convergent Evolution Between the Bamboo-Eating Giant and Red Pandas
    Comparative genomics reveals convergent evolution between the bamboo-eating giant and red pandas Yibo Hua,1,QiWua,1, Shuai Maa,b,1, Tianxiao Maa,b,1, Lei Shana, Xiao Wanga,b, Yonggang Niea, Zemin Ningc, Li Yana, Yunfang Xiud, and Fuwen Weia,b,2 aKey Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; bUniversity of Chinese Academy of Sciences, Beijing 100049, China; cWellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom; and dStraits (Fuzhou) Giant Panda Research and Exchange Center, Fuzhou 350001, China Edited by Steven M. Phelps, University of Texas at Austin, Austin, TX, and accepted by Editorial Board Member Joan E. Strassmann December 15, 2016 (received for review August 19, 2016) Phenotypic convergence between distantly related taxa often mirrors genetic base” (13), and Stephen J. Gould later featured the new adaptation to similar selective pressures and may be driven by genetic digit in the title of his popular 1980 book, “The Panda’sThumb” convergence. The giant panda (Ailuropoda melanoleuca)andred (14). In the red panda, the pseudothumb also facilitates arboreal panda (Ailurus fulgens) belong to different families in the order Car- locomotion (15). Despite this widespread interest, its genetic basis nivora, but both have evolved a specialized bamboo diet and adaptive has remained elusive. These shared characteristics between giant pseudothumb, representing a classic model of convergent evolution. and red pandas represent a classic model of convergent evolution However, the genetic bases of these morphological and physiological under presumably the same environmental pressures. convergences remain unknown.
    [Show full text]
  • The International Mouse Phenotyping Consortium (IMPC): a Functional
    The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation × the IMPC consortium Violeta Muñoz-Fuentes, Pilar Cacheiro, Terrence Meehan, Juan Antonio Aguilar-Pimentel, Steve Brown, Ann Flenniken, Paul Flicek, Antonella Galli, Hamed Haseli Mashhadi, Martin Hrabě de Angelis, et al. To cite this version: Violeta Muñoz-Fuentes, Pilar Cacheiro, Terrence Meehan, Juan Antonio Aguilar-Pimentel, Steve Brown, et al.. The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation × the IMPC consortium. Conservation Genet- ics, Springer Verlag, 2018, 3 (4), pp.995-1005. 10.1007/s10592-018-1072-9. hal-02361601 HAL Id: hal-02361601 https://hal.archives-ouvertes.fr/hal-02361601 Submitted on 13 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Conservation Genetics (2018) 19:995–1005 https://doi.org/10.1007/s10592-018-1072-9 RESEARCH ARTICLE The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation Violeta Muñoz‑Fuentes1 · Pilar Cacheiro2 · Terrence F. Meehan1 · Juan Antonio Aguilar‑Pimentel3 · Steve D. M. Brown4 · Ann M. Flenniken5,6 · Paul Flicek1 · Antonella Galli7 · Hamed Haseli Mashhadi1 · Martin Hrabě de Angelis3,8,9 · Jong Kyoung Kim10 · K.
    [Show full text]
  • Discovering Pharmacogenomic Variants and Pathways with the Epigenome and Spatial Genome
    The Pharmacoepigenomics Informatics Pipeline and H-GREEN Hi-C Compiler: Discovering Pharmacogenomic Variants and Pathways with the Epigenome and Spatial Genome by Ari Lawrence Allyn-Feuer A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Bioinformatics) in the University of Michigan 2018 Doctoral Committee: Professor Brian D. Athey, Chair Assistant Professor Alan P. Boyle Professor Ivo D. Dinov Research Professor Gerald A. Higgins Professor Wolfgang Sadee, The Ohio State University Ari Lawrence Allyn-Feuer [email protected] ORCID iD: 0000-0002-8379-2765 © Ari Allyn-Feuer 2018 Dedication In the epilogue of Altneuland, Theodor Herzl famously wrote: “Dreams are not so different from deeds as some may think. All the deeds of men are dreams at first, and become dreams in the end.” Medical advances undergo a similar progression, from invisible to visible and back. Before they are accomplished, advances in the physician’s art are illegible: no one differentiates from the rest the suffering and death which could be alleviated with methods which do not yet exist. Unavoidable ills have none of the moral force of avoidable ones. Then, for a brief period, beginning shortly before it is deployed in mainstream practice, and slowly concluding over the generation after it becomes widespread, an advance is visible. People see the improvements and celebrate them. Then, subsequently, for the rest of history, if we are lucky, such an advance is more invisible than it was before it was invented. No one tallies the children who do not get polio, the firm ground that used to be a malarial swamp, or the quiet fact of sanitation.
    [Show full text]
  • Formaldehyde Acetaldehyde
    Preventing hereditary cancers caused by op- portunistic carcinogens Bernard Friedenson, Ph.D. Department of Biochemistry and Molecular Genetics College of Medicine 900 S Ashland Ave University of Illinois Chicago, Chicago, IL 60607 Nature Precedings : doi:10.1038/npre.2011.6668.1 Posted 5 Dec 2011 Supported by a grant from the University of Illinois Chicago Running title: Hereditary cancer prevention -1- Objectives Previous studies reported inherited BRCA1/2 deficits can cause cancer by impairing normal protective responses. Opportunistic carcinogens can exploit these deficits by caus- ing chronic inflammation, constant cell death and replacement in a mutagenic environment, DNA crosslinking or double strand breaks. Some of the resulting cancers may be prevented if opportunistic carcinogens are identified. Methods The literature was systematically searched for carcinogens capable of exploiting defi- cits in BRCA1/2 pathways. Search criteria were common exposure, available information, required BRCA1/2 pathway repairs, increased risks for any cancer, and effects on stem cells. Results Formaldehyde and acetaldehyde are closely related carcinogens and common pollut- ants that seem everywhere. Alcohol metabolism also produces acetaldehyde. High levels of either carcinogen overwhelm normal detoxification systems, cause inflammation, inhibit DNA repair and produce DNA cross links as critical carcinogenic lesions. Searching model system studies revealed both carcinogens activate stem cells, BRCA1/2 pathways and con- nected BRCA1/2 pathways to myeloid leukemia. For example, the BRCA1-BARD1 complex is required for proper nucleophosmin functions. Nucleophosmin prevents a major subset of acute myeloid leukemia (AML). Next, these concepts were independently tested against risks for myeloid leukemia. Epidemiologic results showed that BRCA2 gene defects inherited on both chromosomes increased risks so dramatically that AML occurs in most children.
    [Show full text]
  • Genome-Wide Association Study of Alcohol Dependence: Significant findings in African- and European-Americans Including Novel Risk Loci
    Molecular Psychiatry (2014) 19, 41–49 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp IMMEDIATE COMMUNICATION Genome-wide association study of alcohol dependence: significant findings in African- and European-Americans including novel risk loci J Gelernter1,2, HR Kranzler3, R Sherva4, L Almasy5, R Koesterer4, AH Smith1, R Anton6, UW Preuss7, M Ridinger8, D Rujescu7, N Wodarz8, P Zill9, H Zhao10,11 and LA Farrer4,12 We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P ¼ 1.17 Â 10 À 31; AAs: Arg369Cys, P ¼ 6.33 Â 10 À 17) and ADH1C in AAs (Thr151Thr, P ¼ 4.94 Â 10 À 10), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P ¼ 2.63 Â 10 À 11), PDLIM5 in EAs (P ¼ 2.01 Â 10 À 8), and METAP in AAs (P ¼ 3.35 Â 10 À 8). We also identified a novel GWS association (1.17 Â 10 À 10) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19.
    [Show full text]