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.

Key words::

• Genetics
• risk
• DNA

Acknowledgements

We are indebted to the individuals and their families who participated in this project. This study was supported by Federazione Italiana Gioco Calcio and by the Association for ALS research I.CO.M.M. Onlus, Rome, Italy.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.