title: Replication of association of CHRNA4 rare variants with sporadic amyotrophic lateral sclerosis: the Italian multicentre study.
abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels widely expressed throughout the mammalian brain, including bulbar and spinal motor neurons. They are involved in neuroprotection and in control of release of many neurotransmitters, including glutamate. Previous data raised the hypothesis that rare variants in the region coding the intracellular loop subunits of nAChRs might represent one of several genetic risk factors for SALS. The aim of present study was to replicate the study in an independent cohort of ALS patients. We analysed 718 sporadic ALS patients from five Italian ALS centres and 1300 ethnically matched controls. We focused primarily on CHRNA4, encoding α4 subunit, since most mutations were previously detected in this gene. We observed a significant association between CHRNA4 mutations and ALS (OR 2.91; 95% CI 1.4080-6.0453; p = 0.0056). Most mutations detected in patients were not present in the dbSNP134 and in 3500 ethnically matched control chromosomes and affected evolutionary conserved amino acid residues. In conclusion, the present data confirm that CHRNA4 variants are overrepresented in SALS strengthening the hypothesis can they act as predisposing genetic factors for SALS.
authors.affiliation: Istituto di Neurologia, Università Cattolica del Sacro Cuore, Roma, Italy. msabatelli@rm.unicatt.it
authors.forename: Mario
authors.initials: M
authors.lastname: Sabatelli
authors.forename: Serena
authors.initials: S
authors.lastname: Lattante
authors.forename: Amelia
authors.initials: A
authors.lastname: Conte
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marangi
authors.forename: Marco
authors.initials: M
authors.lastname: Luigetti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Del Grande
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.forename: Massimo
authors.initials: M
authors.lastname: Corbo
authors.forename: Fabio
authors.initials: F
authors.lastname: Giannini
authors.forename: Jessica
authors.initials: J
authors.lastname: Mandrioli
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mora
authors.forename: Andrea
authors.initials: A
authors.lastname: Calvo
authors.forename: Gabriella
authors.initials: G
authors.lastname: Restagno
authors.forename: Christian
authors.initials: C
authors.lastname: Lunetta
authors.forename: Silvana
authors.initials: S
authors.lastname: Penco
authors.forename: Stefania
authors.initials: S
authors.lastname: Battistini
authors.forename: Paolo
authors.initials: P
authors.lastname: Zeppilli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bizzarro
authors.forename: Ettore
authors.initials: E
authors.lastname: Capoluongo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: Paolo Maria
authors.initials: PM
authors.lastname: Rossini
authors.forename: Marcella
authors.initials: M
authors.lastname: Zollino
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D016001:Confidence Intervals; D019143:Evolution, Molecular; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016017:Odds Ratio; D011978:Receptors, Nicotinic / Q000235:genetics*; D055815:Young Adult
chemical_list: D011978:Receptors, Nicotinic