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1. Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease

Author

Florentino Sanchez-Garcia, Jean-Charles Lambert, Horacio Scaro, Zulma Sevillano, Paolo Bosco, Wolfgang Maier, Silvia Kochen, Alfredo Ramirez, Laura Morelli, Julieta Lisso, Mariana Soledad Sanchez Avalos, Carlos A Mangone, Cynthia Liberczuk, Paolo Caffarra, Frank Jessen, Daniel Gustavo Politis, Eduardo M. Castaño, Guillermo Jemar, Eliecer Coto, Claudia Kairiyama, Daniela Galimberti, Cristina Fezza, Patrizia Mecocci, Per Hoffmann, Jordi Clarimón, Luis I. Brusco, Claudia Hanses, Paola Bossù, Sandro Sorbi, Benedetta Nacmias, Nancy Medel, Mariana Estela Carulla, Michelangelo Mancuso, Federico A. Prestia, Maria Carolina Dalmasso, Pascual Sánchez-Juan, Pablo Galeano, María J. Bullido, Carolina Muchnik, Martin Ingelsson, Luis Eduardo Martinez, Pablo Javier Azurmendi, Caroline Graff, J Becker, Alberto Pilotto, Marcelo Sampaño, Céline Bellenguez, Maria Fierens, Francesco Panza, Natividad Olivar, Esther Milz, Stefanie Heilmann-Heimbach, Gianfranco Spalletta, Patricia Solís, International Society for Neurochemistry, Alexander von Humboldt Foundation, Agencia Nacional de Promoción Científica y Tecnológica (Argentina), Universidad de Cantabria, and UAM. Departamento de Biología Molecular

Subjects
0301 basic medicine, Male, Neurologi, Genome-wide association study, genetics [Alzheimer Disease], Disease, 0302 clinical medicine, genetics [Membrane Glycoproteins], genetics [Adaptor Proteins, Signal Transducing], purl.org/becyt/ford/3.2 [https], genetics [Black People], TREM2, ethnology [Argentina], genetics [Receptors, Immunologic], Receptors, Immunologic, ABI3 protein, human, Genetics, Aged, 80 and over, Membrane Glycoproteins, Genomics, genetics [African Continental Ancestry Group], Middle Aged, Biología y Biomedicina / Biología, genetics [European Continental Ancestry Group], Neurology, genetics [Phospholipase C gamma], Psychiatry and Mental Health, genetics [Indians, North American], purl.org/becyt/ford/3 [https], Female, Alzheimer's disease, Genotype, ABI3, GENETIC, Argentina, genetics [White People], Black People, Single-nucleotide polymorphism, Biology, DIAGNOSIS, White People, Article, lcsh:RC321-571, PLCG2, 03 medical and health sciences, Cellular and Molecular Neuroscience, Alzheimer Disease, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, ddc:610, Allele frequency, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Genetic association, Aged, Adaptor Proteins, Signal Transducing, ethnology [Alzheimer Disease], TREM2 protein, human, Phospholipase C gamma, Genetic Variation, medicine.disease, 030104 developmental biology, PLCG2, ABI3, TREM2, Indians, North American, Alzheimer, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer’s disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage., International Society for Neurochemistry (ISN) and Alexander von Humboldt Foundation (to M.C.D.); Agencia Nacional de Promoción Científica y Tecnológica (PBIT/09 2013, PICT2015-0285 and PICT-2016-4647 to L.M.; PICT-2014-1537 to M.C.D.)

Published
2019
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2. Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration

Author

Lena Lilius, Linn Öijerstedt, Inger Nennesmo, Marie Westerlund, Håkan Thonberg, Huei-Hsin Chiang, Steinunn Thordardottir, Caroline Graff, Krishnan Shanmugarajan, and Charlotte Forsell

Subjects
Pathology, medicine.medical_specialty, Disease, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, Cohort Studies, Progranulins, mental disorders, Genetics, medicine, Dementia, Humans, Family, Genetic Predisposition to Disease, Mutation frequency, Genetics (clinical), Aged, Aged, 80 and over, Cerebral Cortex, Mutation, Case-control study, nutritional and metabolic diseases, Frontotemporal lobar degeneration, medicine.disease, Immunohistochemistry, nervous system diseases, DNA-Binding Proteins, Case-Control Studies, Intercellular Signaling Peptides and Proteins, Frontotemporal Lobar Degeneration, Haploinsufficiency, Microsatellite Repeats
Abstract

Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease with an age at onset generally below 65 years. Mutations in progranulin (GRN) have been reported to be able to cause FTLD through haploinsufficiency. We have sequenced GRN in 121 patients with FTLD and detected six different mutations in eight patients: p.Gly35Glufs*19, p.Asn118Phefs*4, p.Val200Glyfs*18, p.Tyr294*, p.Cys404* and p.Cys416Leufs*30. Serum was available for five of the mutations, where the serum-GRN levels were found to be >50% reduced compared with FTLD patients without GRN mutations. Moreover, the p.Cys416Leufs*30 mutation segregated in an affected family with different dementia diagnoses. The mutation frequency of GRN mutation was 6.6% in our FTLD cohort.

Published
2013

3. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Author

P. Bosco, Rebecca Sims, Monique M.B. Breteler, L. Concari, Giuseppe Tosto, María J. Bullido, Kristel Sleegers, Fernando Valdivieso, Diana Zelenika, T. Feulner, Raffaele Ferri, Christophe Tzourio, P. Caffara, Davide Seripa, Benjamin Grenier-Boley, Paola Bossù, C. Chillotti, Marc Delepine, C. Deniz-Naranjo, Daniela Galimberti, David-Alexandre Trégouët, Benedetta Nacmias, Elisabeth M. C. Schrijvers, Karolien Bettens, Anne Boland, Christiane Reitz, Florentino Sanchez-Garcia, Dominique Campion, R. Rogers, C. Van Broeckhoven, Jean-Charles Lambert, Denise Harold, Amy Gerrish, Didier Hannequin, Mohammad Arfan Ikram, Michael Conlon O'Donovan, Elio Scarpini, Giorgio Annoni, Vincent Chouraki, Marc Lathrop, Francesco Panza, Chandra A. Reynolds, Gabriele Siciliano, Sandro Sorbi, Philippe Amouyel, Florence Pasquier, Luc Buée, Mikko Hiltunen, Claudine Berr, Eliecer Coto, Victoria Alvarez, Caroline Graff, Vincenzo Solfrizzi, Julie Williams, Jonathan A. Prince, Martin Ingelsson, Michael John Owen, Laura Fratiglioni, Jennifer Chapman, Ignacio Mateo, Annick Alpérovitch, H. Soininen, Michelangelo Mancuso, G. Spalletta, Matthias Riemenschneider, Andrea Pilotto, C. Van Cauwenberghe, Jacques Epelbaum, M. Del Zompo, Onofre Combarros, Lars Lannfelt, Yoichiro Kamatani, Beatrice Arosio, Jean-François Dartigues, Inserm U744, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Cardiff University, Bioinformatics, GlaxoSmithKline, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium, University of Antwerp (UA), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Eastern Finland, G.H. Sergievsky Center, Columbia University, New York, NY, USA, Columbia University Irving Medical Center (CUIMC), Service of Neurology, University Hospital Marques de Valdecilla, University of Cantabria, Santander, Spain, Department of Psychiatry and Psychotherapy, Universitätsklinikum des Saarlandes, Universität des Saarlandes Saarbruecken, Germany, Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Centro Dino Ferrari [Milano], Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Neuroscience, University of Parma, Parma, Italy, Università degli studi di Parma = University of Parma (UNIPR), Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central Asturias, Oviedo, Spain, Servicio de Inmunología. Hospital Unviersitario de Gran Canaria Dr Negrín. Bco, Las Palmas de Gran Canaria, Spain, Department of Geriatrics, Center for aging brain, Memory unit, University of Bari, Bari, Italy, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Department of neurological and psychiatric Sciences, University of Florence, Florence, Italy, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Clinical and Behavioral Neurology, IRCCS Fondazione Santa Lucia, Roma, Italy, Clinical and Behavioral Neurology - Neuroscienze e riabilitazione, IRCCS Fondazione Santa Lucia [Roma], Neurological clinic, University of Pisa, Pisa, Italy, University of Pisa - Università di Pisa, Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden, KI-Alzheimer's Disease Reseach Center, Department NVS, Karolinska Institutet, KIADRC, Stockholm, Sweden, IRCCS Associazione Oasi Maria SS, Institute for Research on Mental Retardation and Brain Aging, Troina (EN), Italy, Department of Psychology [Riverside], University of California [Riverside] (UC Riverside), University of California (UC)-University of California (UC), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Uppsala University, Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, Unit of Clinical Pharmacology, Teaching Hospital of Cagliari, Cagliari, Italy, Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, I.R.C.C.S. 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy, Università degli Studi di Cagliari = University of Cagliari (UniCa), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, DZNE, Bonn, Germany, Génomique cardiovasculaire, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille, the Centre National de Génotypage, Inserm, FRC (fondation sur la recherche sur le cerveau) and Rotary., EADI consortium, GERAD consortium, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli studi di Bari Aldo Moro (UNIBA), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institut de psychiatrie et neurosciences (U894 / UMS 1266), University of California [Riverside] (UCR), University of California-University of California, Section of Clinical Pharmacology, Department of Neurosciences 'B.B. Brodie', University of Cagliari, Cagliari, Italy, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Lambert, J, Grenier Boley, B, Harold, D, Zelenika, D, Chouraki, V, Kamatani, Y, Sleegers, K, Ikram, M, Hiltunen, M, Reitz, C, Mateo, I, Feulner, T, Bullido, M, Galimberti, D, Concari, L, Alvarez, V, Sims, R, Gerrish, A, Chapman, J, Deniz Naranjo, C, Solfrizzi, V, Sorbi, S, Arosio, B, Spalletta, G, Siciliano, G, Epelbaum, J, Hannequin, D, Dartigues, J, Tzourio, C, Berr, C, Schrijvers, E, Rogers, R, Tosto, G, Pasquier, F, Bettens, K, Van Cauwenberghe, C, Fratiglioni, L, Graff, C, Delepine, M, Ferri, R, Reynolds, C, Lannfelt, L, Ingelsson, M, Prince, J, Chillotti, C, Pilotto, A, Seripa, D, Boland, A, Mancuso, M, Bossù, P, Annoni, G, Nacmias, B, Bosco, P, Panza, F, Sanchez Garcia, F, Del Zompo, M, Coto, E, Owen, M, O'Donovan, M, Valdivieso, F, Caffara, P, Scarpini, E, Combarros, O, Buée, L, Campion, D, Soininen, H, Breteler, M, Riemenschneider, M, Van Broeckhoven, C, Alpérovitch, A, Lathrop, M, Trégouët, D, Williams, J, Amouyel, P, Epidemiology, Radiology & Nuclear Medicine, Neurology, Grenier-Boley, Benjamin, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé-Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Departement of Epidemiology and Radiology, Erasmus MC, Rotterdam, Centro de Biologia Molecular Severo Ochoa (UAM-CSIC) and CIBERNED, Universidad Autonoma, Madrid, Spain, Università degli studi di Milano [Milano]-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Internal Medicine, Geriatric Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy, University of Pisa [Pisa], Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Department of Epidemiology and Neurology, Erasmus MC, Rotterdam, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Aging Reasearch Center, Department NVS, Karolinska Institutet and Stockholm University, Stockholm, Sweden, University of California [Riverside] ( UCR ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Department of Epidemiology, Erasmus MC, Rotterdam, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]

Subjects
Apolipoprotein E, haplotype, FERM domain-containing protein 4A, human, genetics [Alzheimer Disease], Genome-wide association study, Disease, Genome, Plasma, 0302 clinical medicine, genetics [Adaptor Proteins, Signal Transducing], blood [Amyloid beta-Peptides], GWAS, genetics [Genetic Predisposition to Disease], [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics, 0303 health sciences, FRMD4A gene, amyloid, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, GWAS study, Alzheimer, FRMD4A, Alzheimer's disease, 3. Good health, Psychiatry and Mental health, Chemistry, genetics [Polymorphism, Single Nucleotide], Original Article, Corrigendum, medicine.medical_specialty, Amyloid, Single-nucleotide polymorphism, Locus (genetics), genome wide haplotype association study, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, blood [Alzheimer Disease], Alzheimer Disease, genetics [Haplotypes], Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Psychiatry, Molecular Biology, plasma, Genetic association, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Amyloid beta-Peptides, business.industry, Haplotype, Case-control study, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Human medicine, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer’s disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n = 2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case– control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P= 1.11010). We finally searched for association between SNPs within the FRMD4A locus and Ab plasma concentrations in three independent non-demented populations (n = 2579). We reported that polymorphisms were associated with plasma Ab42/Ab40 ratio (best signal, P = 5.4107). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Published
2012
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4. Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes

Author

Kristina Åkesson, Johnny Ludvigsson, Sten-Anders Ivarsson, B Van Yserloo, Fredrik Piehl, Jinko Graham, Bengt Lindblad, Samina Asad, Lars Alfredsson, Leonid Padyukov, Ingrid Kockum, Åke Lernmark, Brad McNeney, Mona Landin-Olsson, Marju Orho-Melander, Gun Forsander, Annelie Carlsson, Eero Lindholm, Caroline Graff, Elizabeth A. Rutledge, Maria Swanberg, C Marcus, Tomas Olsson, Charlotte Forsell, Alexandra Gyllenberg, and Helena Elding Larsson

Subjects
Male, age distribution, genetic association, genotype, major histocompatibility antigen class 2, type 1 diabetes (T1D), medicine.disease_cause, genetic risk, Linkage Disequilibrium, Autoimmunity, Gene Frequency, Genotype, genetic variability, Child, Genetics (clinical), Genetics, adult, autoimmunity, Age Factors, CIITA, article, Nuclear Proteins, Basic Medicine, female, priority journal, Child, Preschool, Female, Adult, Adolescent, Monosaccharide Transport Proteins, Immunology, CIITA Gene, chemical and pharmacologic phenomena, CLEC16A, Biology, Polymorphism, Single Nucleotide, insulin dependent diabetes mellitus, White People, male, medicine, Humans, Genetic Predisposition to Disease, Lectins, C-Type, controlled study, human, Allele frequency, Alleles, Genetic association, Sweden, Type 1 diabetes, Infant, Newborn, association, Infant, medicine.disease, major clinical study, human tissue, Diabetes Mellitus, Type 1, age, Case-Control Studies, adolescent, Trans-Activators, transactivator protein
Abstract

The major histocompatibility complex class II transactivator (CIITA) gene (16p13) has been reported to associate with susceptibility to multiple sclerosis, rheumatoid arthritis and myocardial infarction, recently also to celiac disease at genome-wide level. However, attempts to replicate association have been inconclusive. Previously, we have observed linkage to the CIITA region in Scandinavian type 1 diabetes (T1D) families. Here we analyze five Swedish T1D cohorts and a combined control material from previous studies of CIITA. We investigate how the genotype distribution within the CIITA gene varies depending on age, and the association to T1D. Unexpectedly, we find a significant difference in the genotype distribution for markers in CIITA (rs11074932, P=4 × 10(-5) and rs3087456, P=0.05) with respect to age, in the collected control material. This observation is replicated in an independent cohort material of about 2000 individuals (P=0.006, P=0.007). We also detect association to T1D for both markers, rs11074932 (P=0.004) and rs3087456 (P=0.001), after adjusting for age at sampling. The association remains independent of the adjacent T1D risk gene CLEC16A. Our results indicate an age-dependent variation in CIITA allele frequencies, a finding of relevance for the contrasting outcomes of previously published association studies.

Published
2012

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