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

Isabella Fogh; Antonia Ratti; Cinzia Gellera; Kuang Lin; Cinzia Tiloca; Valentina Moskvina; Lucia Corrado; Gianni Sorarù; Cristina Cereda; Stefania Corti; Davide Gentilini; Daniela Calini; Barbara Castellotti; Letizia Mazzini; Giorgia Querin; Stella Gagliardi; Roberto Del Bo; Francesca L Conforti; Gabriele Siciliano; Maurizio Inghilleri; Francesco Saccà; Paolo Bongioanni; Silvana Penco; Massimo Corbo; Sandro Sorbi; Massimiliano Filosto; Alessandra Ferlini; Anna M Di Blasio; Stefano Signorini; Aleksey Shatunov; Ashley Jones; Pamela J Shaw; Karen E Morrison; Anne E Farmer; Philip Van Damme; Wim Robberecht; Adriano Chiò; Bryan J Traynor; Michael Sendtner; Judith Melki; Vincent Meininger; Orla Hardiman; Peter M Andersen; Nigel P Leigh; Jonathan D Glass; Daniel Overste; Frank P Diekstra; Jan H Veldink; Christopher E Shaw; SLAGEN Consortium and Collaborators; Karen Morrison

doi:10.1093/hmg/ddt587

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

Isabella Fogh, Antonia Ratti, Cinzia Gellera, Kuang Lin, Cinzia Tiloca, Valentina Moskvina, Lucia Corrado, Gianni Sorarù, Cristina Cereda, Stefania Corti, Davide Gentilini, Daniela Calini, Barbara Castellotti, Letizia Mazzini, Giorgia Querin, Stella Gagliardi, Roberto Del Bo, Francesca L Conforti, Gabriele Siciliano, Maurizio InghilleriFrancesco Saccà, Paolo Bongioanni, Silvana Penco, Massimo Corbo, Sandro Sorbi, Massimiliano Filosto, Alessandra Ferlini, Anna M Di Blasio, Stefano Signorini, Aleksey Shatunov, Ashley Jones, Pamela J Shaw, Karen E Morrison, Anne E Farmer, Philip Van Damme, Wim Robberecht, Adriano Chiò, Bryan J Traynor, Michael Sendtner, Judith Melki, Vincent Meininger, Orla Hardiman, Peter M Andersen, Nigel P Leigh, Jonathan D Glass, Daniel Overste, Frank P Diekstra, Jan H Veldink, Christopher E Shaw, SLAGEN Consortium and Collaborators, Karen Morrison

Research output: Contribution to journal › Article › peer-review

79 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2220-31
Number of pages	12
Journal	Human Molecular Genetics
Volume	23
Issue number	8
DOIs	https://doi.org/10.1093/hmg/ddt587
Publication status	Published - 15 Apr 2014

Keywords

Amyotrophic Lateral Sclerosis
Case-Control Studies
Chromosomes, Human, Pair 17
Genome-Wide Association Study
Humans
Prognosis

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10.1093/hmg/ddt587

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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 Bo, R., Conforti, F. L., Siciliano, G., ... Morrison, K. (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), 2220-31. https://doi.org/10.1093/hmg/ddt587

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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%) 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.",

keywords = "Amyotrophic Lateral Sclerosis, Case-Control Studies, Chromosomes, Human, Pair 17, Genome-Wide Association Study, Humans, Prognosis",

author = "Isabella Fogh and Antonia Ratti and Cinzia Gellera and Kuang Lin and Cinzia Tiloca and Valentina Moskvina and Lucia Corrado and Gianni Sorar{\`u} and Cristina Cereda and Stefania Corti and Davide Gentilini and Daniela Calini and Barbara Castellotti and Letizia Mazzini and Giorgia Querin and Stella Gagliardi and {Del Bo}, Roberto and Conforti, {Francesca L} and Gabriele Siciliano and Maurizio Inghilleri and Francesco Sacc{\`a} and Paolo Bongioanni and Silvana Penco and Massimo Corbo and Sandro Sorbi and Massimiliano Filosto and Alessandra Ferlini and {Di Blasio}, {Anna M} and Stefano Signorini and Aleksey Shatunov and Ashley Jones and Shaw, {Pamela J} and Morrison, {Karen E} and Farmer, {Anne E} and {Van Damme}, Philip and Wim Robberecht and Adriano Chi{\`o} and Traynor, {Bryan J} and Michael Sendtner and Judith Melki and Vincent Meininger and Orla Hardiman and Andersen, {Peter M} and Leigh, {Nigel P} and Glass, {Jonathan D} and Daniel Overste and Diekstra, {Frank P} and Veldink, {Jan H} and Shaw, {Christopher E} and {SLAGEN Consortium and Collaborators} and Karen Morrison",

year = "2014",

month = apr,

day = "15",

doi = "10.1093/hmg/ddt587",

language = "English",

volume = "23",

pages = "2220--31",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

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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 Bo, R, Conforti, FL, Siciliano, G, Inghilleri, M, Saccà, F, Bongioanni, P, Penco, S, Corbo, M, Sorbi, S, Filosto, M, Ferlini, A, Di Blasio, AM, Signorini, S, Shatunov, A, Jones, A, Shaw, PJ, Morrison, KE, Farmer, AE, Van Damme, P, Robberecht, W, Chiò, A, Traynor, BJ, Sendtner, M, Melki, J, Meininger, V, Hardiman, O, Andersen, PM, Leigh, NP, Glass, JD, Overste, D, Diekstra, FP, Veldink, JH, Shaw, CE, SLAGEN Consortium and Collaborators & Morrison, K 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, no. 8, pp. 2220-31. 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, Isabella

AU - Ratti, Antonia

AU - Gellera, Cinzia

AU - Lin, Kuang

AU - Tiloca, Cinzia

AU - Moskvina, Valentina

AU - Corrado, Lucia

AU - Sorarù, Gianni

AU - Cereda, Cristina

AU - Corti, Stefania

AU - Gentilini, Davide

AU - Calini, Daniela

AU - Castellotti, Barbara

AU - Mazzini, Letizia

AU - Querin, Giorgia

AU - Gagliardi, Stella

AU - Del Bo, Roberto

AU - Conforti, Francesca L

AU - Siciliano, Gabriele

AU - Inghilleri, Maurizio

AU - Saccà, Francesco

AU - Bongioanni, Paolo

AU - Penco, Silvana

AU - Corbo, Massimo

AU - Sorbi, Sandro

AU - Filosto, Massimiliano

AU - Ferlini, Alessandra

AU - Di Blasio, Anna M

AU - Signorini, Stefano

AU - Shatunov, Aleksey

AU - Jones, Ashley

AU - Shaw, Pamela J

AU - Morrison, Karen E

AU - Farmer, Anne E

AU - Van Damme, Philip

AU - Robberecht, Wim

AU - Chiò, Adriano

AU - Traynor, Bryan J

AU - Sendtner, Michael

AU - Melki, Judith

AU - Meininger, Vincent

AU - Hardiman, Orla

AU - Andersen, Peter M

AU - Leigh, Nigel P

AU - Glass, Jonathan D

AU - Overste, Daniel

AU - Diekstra, Frank P

AU - Veldink, Jan H

AU - Shaw, Christopher E

AU - SLAGEN Consortium and Collaborators

AU - Morrison, Karen

PY - 2014/4/15

Y1 - 2014/4/15

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.

KW - Amyotrophic Lateral Sclerosis

KW - Case-Control Studies

KW - Chromosomes, Human, Pair 17

KW - Genome-Wide Association Study

KW - Humans

KW - Prognosis

U2 - 10.1093/hmg/ddt587

DO - 10.1093/hmg/ddt587

M3 - Article

C2 - 24256812

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

Abstract

Keywords

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