Evidence for linkage disequilibrium between the alpha 7-nicotinic receptorgene (CHRNA7) locus and schizophrenia in Azorean families

Recent studies have suggested that the alpha 7-nicotinic receptor gene (CHR NA7) may play a role in the pathogenesis of schizophrenia. The alpha 7-nico tinic receptor gene (CHRNA7) is involved in P50 auditory sensory gating def icits, 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 nove l upstream exons. The marker D15S1360 has been shown to be significantly li nked with the phenotype of abnormal P50 suppression in schizophrenia famili es. 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 t wo L76630 copies is unknown. We genotyped three polymorphic markers D15S136 0, D15S165, and L76630 that are localized in a genomic fragment containing the CHRNA7 in 31 Azorean schizophrenia families/trios (including 41 schizop hrenia individuals and 97 unaffected families members). An overall analysis utilizing the family-based association test revealed significant linkage d isequilibrium between L76630 and schizophrenia (P = 0.0004). Using the exte nded transmission disequilibrium test and limiting the analysis to one tria d 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 syndro me. Therefore, we investigated maternal and paternal meioses. We found sign ificant transmission disequilibrium for D15S1360 through paternal transmiss ion (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 t he CHRNA7 may play a role in schizophrenia in these families. A parent of o rigin effect may be present and requires further Study. Published 2001 Wile y-Liss, Inc.(dagger).