A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

I Fogh; A Ratti; C Gellera; K Lin; C Tiloca; V Moskvina; Lucia CORRADO; G Sorarù; C Cereda; S Corti; D Gentilini; D Calini; B Castellotti; L Mazzini; G Querin; S Gagliardi; Bo R Del; Conforti FL; G Siciliano; M Inghilleri; F Saccà; P Bongioanni; S Penco; M Corbo; S Sorbi; M Filosto; A Ferlini; Di Blasio AM; S Signorini; A Shatunov; A Jones; Shaw PJ; Morrison KE; Farmer AE; Damme P Van; W Robberecht; A Chiò; Traynor BJ; M Sendtner; J Melki; V Meininger; O Hardiman; Andersen PM; Leigh NP; Glass JD; D Overste; Diekstra FP; Veldink JH; van Es MA; Shaw CE; Weale ME; Lewis CM; J Williams; Brown RH; Landers JE; N Ticozzi; M Ceroni; E Pegoraro; Comi GP; Sandra D'ALFONSO; van den Berg LH; F Taroni; Chalabi A Al; J Powell; V Silani; the SLAGEN Consortium; Collaborators

doi:10.1093/hmg/ddt587

A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

I Fogh, A Ratti, C Gellera, K Lin, C Tiloca, V Moskvina, Lucia CORRADO, G Sorarù, C Cereda, S Corti, D Gentilini, D Calini, B Castellotti, L Mazzini, G Querin, S Gagliardi, Bo R Del, Conforti FL, G Siciliano, M InghilleriF Saccà, P Bongioanni, S Penco, M Corbo, S Sorbi, M Filosto, A Ferlini, Di Blasio AM, S Signorini, A Shatunov, A Jones, Shaw PJ, Morrison KE, Farmer AE, Damme P Van, W Robberecht, A Chiò, Traynor BJ, M Sendtner, J Melki, V Meininger, O Hardiman, Andersen PM, Leigh NP, Glass JD, D Overste, Diekstra FP, Veldink JH, van Es MA, Shaw CE, Weale ME, Lewis CM, J Williams, Brown RH, Landers JE, N Ticozzi, M Ceroni, E Pegoraro, Comi GP, Sandra D'ALFONSO, van den Berg LH, F Taroni, Chalabi A Al, J Powell, V Silani, the SLAGEN Consortium, Collaborators

Dipartimento di Scienze della Salute

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

Abstract

.Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90\%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12\% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

Lingua originale	Inglese
pagine (da-a)	2220-2231
Numero di pagine	12
Rivista	Human Molecular Genetics
Volume	23
Numero di pubblicazione	8
DOI	https://doi.org/10.1093/hmg/ddt587
Stato di pubblicazione	Pubblicato - 2014

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10.1093/hmg/ddt587

http://hdl.handle.net/11579/39297

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Fogh, I., Ratti, A., Gellera, C., Lin, K., Tiloca, C., Moskvina, V., CORRADO, L., Sorarù, G., Cereda, C., Corti, S., Gentilini, D., Calini, D., Castellotti, B., Mazzini, L., Querin, G., Gagliardi, S., Del, B. R., FL, C., Siciliano, G., ... Collaborators (2014). A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Human Molecular Genetics, 23(8), 2220-2231. https://doi.org/10.1093/hmg/ddt587

@article{b07e31eeed514623b28443272e329195,

title = "A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis",

abstract = ".Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90\textbackslash{}\%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12\textbackslash{}\% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.",

author = "I Fogh and A Ratti and C Gellera and K Lin and C Tiloca and V Moskvina and Lucia CORRADO and G Sorar{\`u} and C Cereda and S Corti and D Gentilini and D Calini and B Castellotti and L Mazzini and G Querin and S Gagliardi and Del, \{Bo R\} and Conforti FL and G Siciliano and M Inghilleri and F Sacc{\`a} and P Bongioanni and S Penco and M Corbo and S Sorbi and M Filosto and A Ferlini and AM, \{Di Blasio\} and S Signorini and A Shatunov and A Jones and Shaw PJ and Morrison KE and Farmer AE and Van, \{Damme P\} and W Robberecht and A Chi{\`o} and Traynor BJ and M Sendtner and J Melki and V Meininger and O Hardiman and Andersen PM and Leigh NP and Glass JD and D Overste and Diekstra FP and Veldink JH and MA, \{van Es\} and Shaw CE and Weale ME and Lewis CM and J Williams and Brown RH and Landers JE and N Ticozzi and M Ceroni and E Pegoraro and Comi GP and Sandra D'ALFONSO and LH, \{van den Berg\} and F Taroni and Al, \{Chalabi A\} and J Powell and V Silani and Consortium, \{the SLAGEN\} and Collaborators",

note = "Funding Information: The SLAGEN Consortium was supported by funds from the Ministero della Salute Italiano (GWA-SLA, Ricerca Finalizzata 2007 grant number 31) and Fondazione Istituto Auxologico Italiano; I.F., C.G., B.C., J.F.P. and V.S. were supported by the Istituto Superiore di Sanit{\`a} (grant number 526D/34, 2006); I.F. received salary support from {\textquoteleft}Amici del Centro Dino Ferrari{\textquoteright}; V.S. acknowledges support from the {\textquoteleft}Amici del Centro Dino Ferrari{\textquoteright}. A.R., C.G., B.C., N.T. and V.S. were supported by the Ministero della Salute Italiano (ALS-FTD, RF-2009-1473856); G.Si. was supported by Monte dei Paschi di Siena Foundation (grant 39167) and the Ministero della Salute Italiano (grant number RF-INP-2007-627227); A.C. was supported in part by Federazione Italiana Giuoco Calcio and Fondazione Vialli e Mauro per la Sclerosi Laterale Amiotrofica onlus, Ministero della Salute Italiano (grant number RF-PIE-2007-635695); AF was supported by Progetto Regione Emilia Romagna-Universit{\`a} {\textquoteleft}RARER{\textquoteright}. The Italian replica control samples were obtained from the {\textquoteleft}Parkinson Institute Biobank{\textquoteright} (http://www.parkinsonbiobank.com) of the Telethon Genetic Biobank Network (http://www.biobanknetwork.org) supported by TELETHON Italy (grant number GTB07001) and by {\textquoteleft}Fonda-zione Grigioni per il Morbo di Parkinson{\textquoteright}. ALSAGEN Consortium is supported by funds from the National Institutes for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, King{\textquoteright}s College London, the University of Leuven (grant number GOA/11/014), the Interuniversity Attraction Poles (IUAP) program P7/16 of the Belgian Federal Science Policy Office and the 7th Framework Programme of the European Union (ADAMS project, grant numbers HEALTH-F4-2009-242257 and FP7/2007-2013, grant agreements 259867 and 278611). P.V.D. holds a clinical investigatorship from FWO-Vlaanderen; W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders. The UK National DNA Bank for Motor Neuron Disease Research was funded by the Motor Neurone Disease Association (grant 3/3), the Wellcome Trust (grant number 070122/A/02/Z) and the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network. A.A.-C. and J.F.P. receive salary support from the National Institute for Health Research Dementia Biomedical Research Unit at South London and Maudsley National Health Service Foundation Trust and King{\textquoteright}s College London. The RADIANT depression and bipolar case control studies (DeCC, BACC) were genotyped under Medical Research Council (grant number G0701420). A.A.-C. thanks the Motor Neurone Disease Association of Great Britain and Northern Ireland, the ALS Association, the ALS Therapy Alliance and the Medical Research Council (grant number G0600974) for support. R.H.B. acknowledges support from the National Institute of Neurological Disorders and Stroke (grant number 5RO1-NS050557-05) and the National Institute of Neurological Disorders and Stroke American Recovery and Reinvestment Act Award (grant number RC2-NS070-342), the Angel Fund, the ALS Association, P2ALS, Project ALS, the Pierre L. de Bourg-knecht ALS Research Foundation and the ALS Therapy Alliance. J.E.L. acknowledges grant support from National Institute of Health/ National Institute of Neurological Disorders and Stroke (grant number 1R01NS073873). The Dutch, Belgian and Swedish GWAS data generation was supported by the Prinses Beatrix Fonds, VSB fonds, H. Kersten and M. Kersten (Kersten Foundation), The Netherlands ALS Foundation, and J.R. van Dijk and the Adessium Foundation. Funding Information: Genetic and statistical analysis was performed using a Linux cluster supported by the National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry King{\textquoteright}s College London. G.So. acknowledges EuroBiobank for ALS DNA samples; K.M. acknowledges Motor Neurone Disease Association UK, Queen Elizabeth Hospital Birmingham Charity. M.S. acknowledges support through EU via the Euro-MOTOR consortium and German BMBF Motoneuron disease network.",

year = "2014",

doi = "10.1093/hmg/ddt587",

language = "English",

volume = "23",

pages = "2220--2231",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "8",

}

Fogh, I, Ratti, A, Gellera, C, Lin, K, Tiloca, C, Moskvina, V, CORRADO, L, Sorarù, G, Cereda, C, Corti, S, Gentilini, D, Calini, D, Castellotti, B, Mazzini, L, Querin, G, Gagliardi, S, Del, BR, FL, C, Siciliano, G, Inghilleri, M, Saccà, F, Bongioanni, P, Penco, S, Corbo, M, Sorbi, S, Filosto, M, Ferlini, A, AM, DB, Signorini, S, Shatunov, A, Jones, A, PJ, S, KE, M, AE, F, Van, DP, Robberecht, W, Chiò, A, BJ, T, Sendtner, M, Melki, J, Meininger, V, Hardiman, O, PM, A, NP, L, JD, G, Overste, D, FP, D, JH, V, MA, VE, CE, S, ME, W, CM, L, Williams, J, RH, B, JE, L, Ticozzi, N, Ceroni, M, Pegoraro, E, GP, C, D'ALFONSO, S, LH, VDB, Taroni, F, Al, CA, Powell, J, Silani, V, Consortium, TSLAGEN & Collaborators 2014, 'A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis', Human Molecular Genetics, vol. 23, n. 8, pagg. 2220-2231. https://doi.org/10.1093/hmg/ddt587

TY - JOUR

T1 - A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

AU - Fogh, I

AU - Ratti, A

AU - Gellera, C

AU - Lin, K

AU - Tiloca, C

AU - Moskvina, V

AU - CORRADO, Lucia

AU - Sorarù, G

AU - Cereda, C

AU - Corti, S

AU - Gentilini, D

AU - Calini, D

AU - Castellotti, B

AU - Mazzini, L

AU - Querin, G

AU - Gagliardi, S

AU - Del, Bo R

AU - FL, Conforti

AU - Siciliano, G

AU - Inghilleri, M

AU - Saccà, F

AU - Bongioanni, P

AU - Penco, S

AU - Corbo, M

AU - Sorbi, S

AU - Filosto, M

AU - Ferlini, A

AU - AM, Di Blasio

AU - Signorini, S

AU - Shatunov, A

AU - Jones, A

AU - PJ, Shaw

AU - KE, Morrison

AU - AE, Farmer

AU - Van, Damme P

AU - Robberecht, W

AU - Chiò, A

AU - BJ, Traynor

AU - Sendtner, M

AU - Melki, J

AU - Meininger, V

AU - Hardiman, O

AU - PM, Andersen

AU - NP, Leigh

AU - JD, Glass

AU - Overste, D

AU - FP, Diekstra

AU - JH, Veldink

AU - MA, van Es

AU - CE, Shaw

AU - ME, Weale

AU - CM, Lewis

AU - Williams, J

AU - RH, Brown

AU - JE, Landers

AU - Ticozzi, N

AU - Ceroni, M

AU - Pegoraro, E

AU - GP, Comi

AU - D'ALFONSO, Sandra

AU - LH, van den Berg

AU - Taroni, F

AU - Al, Chalabi A

AU - Powell, J

AU - Silani, V

AU - Consortium, the SLAGEN

AU - Collaborators, null

N1 - Funding Information: The SLAGEN Consortium was supported by funds from the Ministero della Salute Italiano (GWA-SLA, Ricerca Finalizzata 2007 grant number 31) and Fondazione Istituto Auxologico Italiano; I.F., C.G., B.C., J.F.P. and V.S. were supported by the Istituto Superiore di Sanità (grant number 526D/34, 2006); I.F. received salary support from ‘Amici del Centro Dino Ferrari’; V.S. acknowledges support from the ‘Amici del Centro Dino Ferrari’. A.R., C.G., B.C., N.T. and V.S. were supported by the Ministero della Salute Italiano (ALS-FTD, RF-2009-1473856); G.Si. was supported by Monte dei Paschi di Siena Foundation (grant 39167) and the Ministero della Salute Italiano (grant number RF-INP-2007-627227); A.C. was supported in part by Federazione Italiana Giuoco Calcio and Fondazione Vialli e Mauro per la Sclerosi Laterale Amiotrofica onlus, Ministero della Salute Italiano (grant number RF-PIE-2007-635695); AF was supported by Progetto Regione Emilia Romagna-Università ‘RARER’. The Italian replica control samples were obtained from the ‘Parkinson Institute Biobank’ (http://www.parkinsonbiobank.com) of the Telethon Genetic Biobank Network (http://www.biobanknetwork.org) supported by TELETHON Italy (grant number GTB07001) and by ‘Fonda-zione Grigioni per il Morbo di Parkinson’. ALSAGEN Consortium is supported by funds from the National Institutes for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, King’s College London, the University of Leuven (grant number GOA/11/014), the Interuniversity Attraction Poles (IUAP) program P7/16 of the Belgian Federal Science Policy Office and the 7th Framework Programme of the European Union (ADAMS project, grant numbers HEALTH-F4-2009-242257 and FP7/2007-2013, grant agreements 259867 and 278611). P.V.D. holds a clinical investigatorship from FWO-Vlaanderen; W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders. The UK National DNA Bank for Motor Neuron Disease Research was funded by the Motor Neurone Disease Association (grant 3/3), the Wellcome Trust (grant number 070122/A/02/Z) and the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network. A.A.-C. and J.F.P. receive salary support from the National Institute for Health Research Dementia Biomedical Research Unit at South London and Maudsley National Health Service Foundation Trust and King’s College London. The RADIANT depression and bipolar case control studies (DeCC, BACC) were genotyped under Medical Research Council (grant number G0701420). A.A.-C. thanks the Motor Neurone Disease Association of Great Britain and Northern Ireland, the ALS Association, the ALS Therapy Alliance and the Medical Research Council (grant number G0600974) for support. R.H.B. acknowledges support from the National Institute of Neurological Disorders and Stroke (grant number 5RO1-NS050557-05) and the National Institute of Neurological Disorders and Stroke American Recovery and Reinvestment Act Award (grant number RC2-NS070-342), the Angel Fund, the ALS Association, P2ALS, Project ALS, the Pierre L. de Bourg-knecht ALS Research Foundation and the ALS Therapy Alliance. J.E.L. acknowledges grant support from National Institute of Health/ National Institute of Neurological Disorders and Stroke (grant number 1R01NS073873). The Dutch, Belgian and Swedish GWAS data generation was supported by the Prinses Beatrix Fonds, VSB fonds, H. Kersten and M. Kersten (Kersten Foundation), The Netherlands ALS Foundation, and J.R. van Dijk and the Adessium Foundation. Funding Information: Genetic and statistical analysis was performed using a Linux cluster supported by the National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry King’s College London. G.So. acknowledges EuroBiobank for ALS DNA samples; K.M. acknowledges Motor Neurone Disease Association UK, Queen Elizabeth Hospital Birmingham Charity. M.S. acknowledges support through EU via the Euro-MOTOR consortium and German BMBF Motoneuron disease network.

PY - 2014

Y1 - 2014

N2 - .Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90\%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12\% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

AB - .Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90\%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12\% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

UR - https://iris.uniupo.it/handle/11579/39297

U2 - 10.1093/hmg/ddt587

DO - 10.1093/hmg/ddt587

M3 - Article

SN - 0964-6906

VL - 23

SP - 2220

EP - 2231

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 8

ER -

A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

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