M Federoff1, T R Price2, A Sailer3, S Scholz4, D Hernandez2, A Nicolas2, A B Singleton2, M Nalls2, H Houlden3. 1. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address: monica.federoff22@gmail.com. 2. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. 3. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. 4. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA; Neurodegenerative Diseases Research Group, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract
INTRODUCTION: Multiple System Atrophy (MSA) is a neurodegenerative disease which presents heterogeneously with symptoms and signs of parkinsonism, ataxia and autonomic dysfunction. Although MSA typically occurs sporadically, rare pathology-proven MSA families following either autosomal recessive or autosomal dominant patterns have been described, indicating a heritable contribution to the pathogenesis. METHODS: We used Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable component of MSA due to common coding variability in imputed genotype data of 907 MSA cases and 3866 population-matched controls. GCTA only assesses the effect of putative causal variants in linkage disequilibrium (LD) with all common SNPs on the genotyping platform. RESULTS: We estimate the heritability among common variants of MSA in pooled cases at 2.09-6.65%, with a wider range of values in geographic and diagnostic subgroups. Meta-analysis of our geographic cohorts reveals high between-group heterogeneity. Contributions of single chromosomes are generally negligible. We suggest that all calculated MSA heritability among common variants could be explained by the presence of misdiagnosed cases in the clinical subgroup based on a Bayesian estimate using literature-derived rates of misdiagnosis. DISCUSSION: MSA is a challenging disease to study due to high rates of misdiagnosis and low prevalence. Given our low estimates of heritability, common genetic variation appears to play a less prominent role in risk for MSA than in other complex neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. The success of future gene discovery efforts rests on large pathologically-confirmed case series and an interrogation of both common and rare genetic variants. Published by Elsevier Ltd.
INTRODUCTION: Multiple System Atrophy (MSA) is a neurodegenerative disease which presents heterogeneously with symptoms and signs of parkinsonism, ataxia and autonomic dysfunction. Although MSA typically occurs sporadically, rare pathology-proven MSA families following either autosomal recessive or autosomal dominant patterns have been described, indicating a heritable contribution to the pathogenesis. METHODS: We used Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable component of MSA due to common coding variability in imputed genotype data of 907 MSA cases and 3866 population-matched controls. GCTA only assesses the effect of putative causal variants in linkage disequilibrium (LD) with all common SNPs on the genotyping platform. RESULTS: We estimate the heritability among common variants of MSA in pooled cases at 2.09-6.65%, with a wider range of values in geographic and diagnostic subgroups. Meta-analysis of our geographic cohorts reveals high between-group heterogeneity. Contributions of single chromosomes are generally negligible. We suggest that all calculated MSA heritability among common variants could be explained by the presence of misdiagnosed cases in the clinical subgroup based on a Bayesian estimate using literature-derived rates of misdiagnosis. DISCUSSION: MSA is a challenging disease to study due to high rates of misdiagnosis and low prevalence. Given our low estimates of heritability, common genetic variation appears to play a less prominent role in risk for MSA than in other complex neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. The success of future gene discovery efforts rests on large pathologically-confirmed case series and an interrogation of both common and rare genetic variants. Published by Elsevier Ltd.
Entities:
Keywords:
Atypical parkinsonisms; Genetics; Multiple System Atrophy
Authors: Shaun Purcell; Benjamin Neale; Kathe Todd-Brown; Lori Thomas; Manuel A R Ferreira; David Bender; Julian Maller; Pamela Sklar; Paul I W de Bakker; Mark J Daly; Pak C Sham Journal: Am J Hum Genet Date: 2007-07-25 Impact factor: 11.025
Authors: Margaux F Keller; Luigi Ferrucci; Andrew B Singleton; Pentti J Tienari; Hannu Laaksovirta; Gabriella Restagno; Adriano Chiò; Bryan J Traynor; Michael A Nalls Journal: JAMA Neurol Date: 2014-09 Impact factor: 18.302
Authors: J C Lambert; C A Ibrahim-Verbaas; D Harold; A C Naj; R Sims; C Bellenguez; A L DeStafano; J C Bis; G W Beecham; B Grenier-Boley; G Russo; T A Thorton-Wells; N Jones; A V Smith; V Chouraki; C Thomas; M A Ikram; D Zelenika; B N Vardarajan; Y Kamatani; C F Lin; A Gerrish; H Schmidt; B Kunkle; M L Dunstan; A Ruiz; M T Bihoreau; S H Choi; C Reitz; F Pasquier; C Cruchaga; D Craig; N Amin; C Berr; O L Lopez; P L De Jager; V Deramecourt; J A Johnston; D Evans; S Lovestone; L Letenneur; F J Morón; D C Rubinsztein; G Eiriksdottir; K Sleegers; A M Goate; N Fiévet; M W Huentelman; M Gill; K Brown; M I Kamboh; L Keller; P Barberger-Gateau; B McGuiness; E B Larson; R Green; A J Myers; C Dufouil; S Todd; D Wallon; S Love; E Rogaeva; J Gallacher; P St George-Hyslop; J Clarimon; A Lleo; A Bayer; D W Tsuang; L Yu; M Tsolaki; P Bossù; G Spalletta; P Proitsi; J Collinge; S Sorbi; F Sanchez-Garcia; N C Fox; J Hardy; M C Deniz Naranjo; P Bosco; R Clarke; C Brayne; D Galimberti; M Mancuso; F Matthews; S Moebus; P Mecocci; M Del Zompo; W Maier; H Hampel; A Pilotto; M Bullido; F Panza; P Caffarra; B Nacmias; J R Gilbert; M Mayhaus; L Lannefelt; H Hakonarson; S Pichler; M M Carrasquillo; M Ingelsson; D Beekly; V Alvarez; F Zou; O Valladares; S G Younkin; E Coto; K L Hamilton-Nelson; W Gu; C Razquin; P Pastor; I Mateo; M J Owen; K M Faber; P V Jonsson; O Combarros; M C O'Donovan; L B Cantwell; H Soininen; D Blacker; S Mead; T H Mosley; D A Bennett; T B Harris; L Fratiglioni; C Holmes; R F de Bruijn; P Passmore; T J Montine; K Bettens; J I Rotter; A Brice; K Morgan; T M Foroud; W A Kukull; D Hannequin; J F Powell; M A Nalls; K Ritchie; K L Lunetta; J S Kauwe; E Boerwinkle; M Riemenschneider; M Boada; M Hiltuenen; E R Martin; R Schmidt; D Rujescu; L S Wang; J F Dartigues; R Mayeux; C Tzourio; A Hofman; M M Nöthen; C Graff; B M Psaty; L Jones; J L Haines; P A Holmans; M Lathrop; M A Pericak-Vance; L J Launer; L A Farrer; C M van Duijn; C Van Broeckhoven; V Moskvina; S Seshadri; J Williams; G D Schellenberg; P Amouyel Journal: Nat Genet Date: 2013-10-27 Impact factor: 38.330
Authors: Judith A Potashkin; Jose A Santiago; Bernard M Ravina; Arthur Watts; Alexey A Leontovich Journal: PLoS One Date: 2012-08-27 Impact factor: 3.240
Authors: Iva Stankovic; Niall Quinn; Luca Vignatelli; Angelo Antonini; Daniela Berg; Elizabeth Coon; Pietro Cortelli; Alessandra Fanciulli; Joaquim J Ferreira; Roy Freeman; Glenda Halliday; Günter U Höglinger; Valeria Iodice; Horacio Kaufmann; Thomas Klockgether; Vladimir Kostic; Florian Krismer; Anthony Lang; Johannes Levin; Phillip Low; Christopher Mathias; Wassillios G Meissner; Lucy Norcliffe Kaufmann; Jose-Alberto Palma; Jalesh N Panicker; Maria Teresa Pellecchia; Ryuji Sakakibara; Jeremy Schmahmann; Sonja W Scholz; Wolfgang Singer; Maria Stamelou; Eduardo Tolosa; Shoji Tsuji; Klaus Seppi; Werner Poewe; Gregor K Wenning Journal: Mov Disord Date: 2019-04-29 Impact factor: 10.338
Authors: Monica Diez-Fairen; Sara Bandres-Ciga; Gabrielle Houle; Mike A Nalls; Simon L Girard; Patrick A Dion; Cornelis Blauwendraat; Andrew B Singleton; Guy A Rouleau; Pau Pastor Journal: Parkinsonism Relat Disord Date: 2019-05-04 Impact factor: 4.891
Authors: J Brettschneider; D J Irwin; S Boluda; M D Byrne; L Fang; E B Lee; J L Robinson; E Suh; V M Van Deerlin; J B Toledo; M Grossman; H Hurtig; R Dengler; S Petri; V M-Y Lee; J Q Trojanowski Journal: Neuropathol Appl Neurobiol Date: 2016-10-18 Impact factor: 8.090
Authors: Catherine Labbé; Michael G Heckman; Oswaldo Lorenzo-Betancor; Melissa E Murray; Kotaro Ogaki; Alexandra I Soto-Ortolaza; Ronald L Walton; Shinsuke Fujioka; Shunsuke Koga; Ryan J Uitti; Jay A van Gerpen; Ronald C Petersen; Neill R Graff-Radford; Steven G Younkin; Bradley F Boeve; William P Cheshire; Phillip A Low; Paola Sandroni; Elizabeth A Coon; Wolfgang Singer; Zbigniew K Wszolek; Dennis W Dickson; Owen A Ross Journal: Parkinsonism Relat Disord Date: 2016-06-16 Impact factor: 4.891
Authors: Anna Sailer; Sonja W Scholz; Michael A Nalls; Claudia Schulte; Monica Federoff; T Ryan Price; Andrew Lees; Owen A Ross; Dennis W Dickson; Kin Mok; Niccolo E Mencacci; Lucia Schottlaender; Viorica Chelban; Helen Ling; Sean S O'Sullivan; Nicholas W Wood; Bryan J Traynor; Luigi Ferrucci; Howard J Federoff; Timothy R Mhyre; Huw R Morris; Günther Deuschl; Niall Quinn; Hakan Widner; Alberto Albanese; Jon Infante; Kailash P Bhatia; Werner Poewe; Wolfgang Oertel; Günter U Höglinger; Ullrich Wüllner; Stefano Goldwurm; Maria Teresa Pellecchia; Joaquim Ferreira; Eduardo Tolosa; Bastiaan R Bloem; Olivier Rascol; Wassilios G Meissner; John A Hardy; Tamas Revesz; Janice L Holton; Thomas Gasser; Gregor K Wenning; Andrew B Singleton; Henry Houlden Journal: Neurology Date: 2016-09-14 Impact factor: 9.910