Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families

Abstract

Recent reports have strongly linked markers near the alpha-7 nicotinic cholinergic receptor subunit gene on human chromosome 15q13-q14 to a sensory gating deficit common in schizophrenics, and have shown positive though non-significant results linking this region to the primary phenotype of schizophrenia in a sample of North American families. We therefore tested for linkage between markers in this region of chromosome 15q and schizophrenia in a sample of 15 multiply affected and 5 single case families with schizophrenia drawn from the Bantu-speaking black population of South Africa. An initial replication using markers from the original study gave an affected-only LOD score maximum of 1.08 under a recessive model at Theta=0.00 for D15S1360, a dinucleotide polymorphism found on the same YAC as the alpha-7 receptor gene. Nonparametric affected-only multipoint analysis gave a Z-score of 1. 29, P=0.098, for D15S1360, and Z=1.45, p=0.075 for D15S118. We then increased the resolution of the map with an extended set of 20 markers. Again, two peaks were observed, with NPL scores of 1.81, p=0.037, at D15S1043 and 1.79 at D15S1360 and 1.80 at D15S1010, both p=0.037. Transmission disequilibrium testing of data from D15S1360 gave an allele-wise and genotype-wise chi(2) of 6.59, 2 df, p=0.037. Haplotype transmission disequilibrium testing using a restricted allele and haplotype set from D15S1043 and D15S1360 gave a global chi(2) of 10.647, 4 df, P=0.007, and a maximum chi(2) of 6.567, 1 df, P=0.004 for excess transmission of the 1.2 haplotype into affected offspring. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:196-201, 2000.

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism

“…32 Freedman et al 33 reported positive linkage of the abnormality in P50 suppression with D15S1360, a dinucleotide repeat present o120 kbp from the 5 0 end of the coding region of the alpha 7-nicotinic receptor gene (CHRNA-7), assuming an autosomal dominant mode of transmission (LOD score ¼ 5.3, Y ¼ 0.0, Po0.0001 33 ). This linkage has been replicated in several other populations including African Americans, 31 Germans, 32 Southern African Bantu families 34 and Taiwanese. 35 Several other studies have also pointed towards this region as being of significance for psychiatric disorders.…”

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].…”

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

“…The P50 sensory gating deficit, one of the best supported endophenotypes of schizophrenia and bipolar disorder, is strongly linked to this region, 1 as are two idiopathic epilepsies. 2,3 Of the many attempts to demonstrate linkage of schizophrenia and bipolar disorder to this region, two studies showed linkage to bipolar disorder, 4,5 but several found either weak [6][7][8][9][10] or no linkage to schizophrenia. [11][12][13] Both schizophrenia and bipolar disorder have also shown association with 15q13.3 markers.…”