Evidence for linkage disequilibrium between the alpha 7‐nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families*

Abstract

Recent studies have suggested that the alpha 7-nicotinic receptor gene (CHRNA7) may play a role in the pathogenesis of schizophrenia. The alpha 7-nicotinic receptor gene (CHRNA7) is involved in P50 auditory sensory gating deficits, and the genomic locus for this gene lies in the chromosome 15q13-14 regions. The human gene is partially duplicated (exons 5-10) with four novel upstream exons. The marker D15S1360 has been shown to be significantly linked with the phenotype of abnormal P50 suppression in schizophrenia families. The marker L76630 is 3 kb in the 3' direction from the last exon of the CHRNA7 gene and is located in the duplicated region. The function of the two L76630 copies is unknown. We genotyped three polymorphic markers D15S1360, D15S165, and L76630 that are localized in a genomic fragment containing the CHRNA7 in 31 Azorean schizophrenia families/trios (including 41 schizophrenia individuals and 97 unaffected families members). An overall analysis utilizing the family-based association test revealed significant linkage disequilibrium between L76630 and schizophrenia (P = 0.0004). Using the extended transmission disequilibrium test and limiting the analysis to one triad per family, transmission disequilibrium of D15S1360 was near significance (P = 0.078). The 15q13 region overlaps with the location of two well-known genomically imprinted disorders: Angelman syndrome and Prader-Willi syndrome. Therefore, we investigated maternal and paternal meioses. We found significant transmission disequilibrium for D15S1360 through paternal transmission (P = 0.0006) in our schizophrenia families. The L76630 marker showed a significant disequilibrium in maternal transmissions (P = 0.028). No parent-of-origin effect was found in D15S165. Overall, our results suggest that the CHRNA7 may play a role in schizophrenia in these families. A parent of origin effect may be present and requires further study.

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

“…0.001) was for marker D15S1360, which is physically close to the ·-7 nicotinic acetylcholine receptor (nAChR) subunit gene (CHRNA7). Additional studies using 15q14 markers have implicated CHRNA7 in schizophrenia using linkage [Coon et al, 1994;Riley et al, 1997;Kaufmann et al, 1998;Leonard et al, 1998;Gejman et al, 2001;Liu et al, 2001;Tsuang et al, 2001] and linkage disequilibrium methods [Riley et al, 2000;Stassen et al, 2000;Freedman et al, 2001;Xu et al, 2001]. In contrast, several studies have not confirmed these results [Moises et al, 1995;Pulver et al, 1995;Faraone et al, 1998;Levinson et al, 1998;Neves-Pereira et al, 1998;Curtis et al, 1999;Hovatta et al, 1999;Ekelund et al, 2000;Gurling et al, 2001].…”

“…The individual gene analysis further targets specific genes that may have particular involvement, those being CHRNA2, CHRNB2, and possibly CHRNA7 and CHRNA1. Although more research is necessary, the results for CHRNA7 are compelling because this gene has been implicated in schizophrenia and sensory gating deficits by several prior studies [Coon et al, 1994;Freedman et al, 1997Freedman et al, , 2001Riley et al, 1997Riley et al, , 2000Leonard et al, 1998;Stassen et al, 2000;Gejman et al, 2001;Liu et al, 2001;Tsuang et al, 2001;Xu et al, 2001]. Both the complex and individual analyses helps to further prioritize genes for case control studies relating to smoking in schizophrenics.…”

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

“…Maximal linkage to the P50 deficit was found at chromosome 15q14 at a polymorphic marker < 120 kb from the α7 gene with a lod score of 5.3, Θ = 0.0 [39]. Linkage of this region to schizophrenia was further replicated in families from the NIMH Schizophrenia Genetics Initiative [40] and in other studies [41,42,43,44], but there have also been some negative studies in this region [45,46]. Multiple single nucleotide polymorphisms (SNP)have been identified in the 15q14 gene promoter region that are more frequently present in people with schizophrenia and their family members than normal controls [47,48].…”

Genetics of Smoking and Schizophrenia

“…The locus of the α7 subunit, 15q14, has also been linked to the P50 deficit in schizophrenia with a LOD score of 5.3 . Linkage of this site to schizophrenia has been replicated in multiple studies (Freedman et al, 2001a;Freedman et al, 2001b;Leonard et al, 1998;Xu et al, 2001;Liu et al, 2001;Tsuang et al, 2001;Kaufmann et al, 1998;Stober et al, 2000;Riley et al, 2000). A linkage of smoking in schizophrenia to a dinucleotide repeat in intron 2 of the α7 gene, CHRNA7, was recently reported (De Luca et al, 2004), further supporting a role for the α7* receptor in smoking in schizophrenia.…”