A Novel Permutation Testing Method Implicates Sixteen Nicotinic Acetylcholine Receptor Genes as Risk Factors for Smoking in Schizophrenia Families

Abstract

Smoking is a common correlate of schizophrenia, which leads to medical morbidity. Although twin and adoption studies have consistently implicated genes in the etiology of both smoking and schizophrenia, finding genes has been difficult. Several authors have suggested that clinical or neurobiological features associated with schizophrenia, such as smoking, might improve the ability to detect schizophrenia susceptibility genes by identifying genes related to the etiology of that feature. The objective of this study is to assess evidence for linkage of sixteen nicotinic acetylcholine receptor genes and smoking in schizophrenia families, using data from the NIMH Genetics Initiative for schizophrenia. Sixteen nicotinic acetylcholine receptor genes were selected prior to analysis. We used a multipoint sibling pair linkage analysis program, SIBPAL2, with a smoking trait in schizophrenia families. The significance of the group of candidate genes, in addition to each individual candidate gene, was assessed using permutation testing, which adjusted for multiple comparisons. The group of genes showed significant linkage to the smoking trait after adjusting for multiple comparisons through permutation testing (p = 0.039). In addition, two of the individual candidate genes were significant (CHRNA2, p = 0.044) and (CHRNB2, p = 0.015) and two genes were marginally significant (CHRNA7, p = 0.095; CHRNA1, p = 0.076). The significance of the complex hypothesis, involving sixteen genes, implicates the nicotinic system in smoking for schizophrenic families. Individual gene analysis suggests that CHRNA2 and CHRNB2 may play a particular role in this involvement. Such findings help prioritize genes for future case control studies. In addition, we provide a novel permutation method that is useful in future analyses involving a single hypothesis, with multiple candidate genes.

Association of candidate genes with antisocial drug dependence in adolescents

“…Although CHRNA2 had been previously implicated in nicotine dependence in schizophrenic families (Faraone et al, 2004), evidence for a contribution of CHRNA2 to antisocial drug dependence is novel. However, evidence for a role of brain-expressed neuronal nicotinic receptors on substance dependence is quickly accumulating.…”

Nicotine Effect on Prepulse Inhibition and Prepulse Facilitation in Schizophrenia Patients

“…In rodents, a4b2 subunit of nAChRs, but not a7, appears to regulate acoustic PPI (Schreiber et al, 2002). However, there is strong evidence suggesting that a7 nAChR (for a recent review see Martin and Freedman, 2007) and to a lesser extent a4b2 nAChR (Breese et al, 2000;Durany et al, 2000;Marutle et al, 2001;Faraone et al, 2004;De Luca et al, 2006) are involved in the pathology of schizophrenia. Subtype-specific nAChRs compounds are now becoming available for human studies.…”

Prioritization of Positional Candidate Genes Using Multiple Web-Based Software Tools

“…Interestingly, in the case of schizophrenia, all programs identify the same candidate gene for all regions, and it is not the one expected. The candidate gene identified, CHRNA2, has been reported as not increasing the susceptibility to schizophrenia, according to one study by Blaveri et al (2001), but may play a particular role in the nicotinic system in smoking for schizophrenic families, according to another study by Faraone et al (2004). By limiting the mean total ranking of the three software tools to the 10 Mb region, three of four of the expected candidate genes are ranked as the most probable.…”