The nicotinic acetylcholine receptor alpha 4 subunit contains a functionally relevant SNP Haplotype.
BACKGROUND
Non-coding single nucleotide polymorphisms within the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4) are robustly associated with various neurological and behavioral phenotypes including schizophrenia, cognition and smoking. The most commonly associated polymorphisms are located in exon 5 and segregate as part of a haplotype. So far it is unknown if this haplotype is indeed functional, or if the observed associations are an indirect effect caused by linkage disequilibrium with not yet identified adjacent functional variants. We therefore analyzed the functional relevance of the exon 5 haplotype alleles.


RESULTS
Using voltage clamp experiments we were able to show that the CHRNA4 haplotype alleles differ with respect to their functional effects on receptor sensitivity including reversal of receptor sensitivity between low and high acetylcholine concentrations. The results indicate that underlying mechanisms might include differences in codon usage bias and changes in mRNA stability.


CONCLUSIONS
Our data demonstrate that the complementary alleles of the CHRNA4 exon 5 haplotype are functionally relevant, and might therefore be causative for the above mentioned associations.
Marlene Eggert, Institute of Human Genetics, Ludwig-Maximilians-University Hospital, 80336, Munich, Germany. Marlene.Eggert@med.uni-muenchen.de.
Marlene
M
Eggert
Georg Winterer, Experimental and Clinical Research Center (ECRC), Charité - University Medicine Berlin, Berlin, Germany. Georg.Winterer@charite.de.
Georg
G
Winterer
Mario Wanischeck, Institute of Human Genetics, Ludwig-Maximilians-University Hospital, 80336, Munich, Germany. Mario.Wanischeck@med.uni-muenchen.de.
Mario
M
Wanischeck
Jean-Charles Hoda, SwissCheckUp SA, 1400, Yverdon-Les-Bains, Switzerland. jean-charles.hoda@swisscheckup.com.
Jean-Charles
JC
Hoda
Daniel Bertrand, HiQScreen, 1222, Vésenaz, Geneva, Switzerland. daniel.bertrand@hiqscreen.com.
Daniel
D
Bertrand
Ortrud K Steinlein, Institute of Human Genetics, Ludwig-Maximilians-University Hospital, 80336, Munich, Germany. Ortrud.Steinlein@med.uni-muenchen.de.
Ortrud
O
Steinlein
D000483:Alleles; D003062:Codon; D005091:Exons; D015870:Gene Expression; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D009690:Nucleic Acid Conformation; D020641:Polymorphism, Single Nucleotide; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism
D003062:Codon; D012333:RNA, Messenger; D011978:Receptors, Nicotinic