PubMed · 14246764
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G EDWARDS. 1964. THE CIRCULATING ALCOHOLIC.. https://doi.org/10.1177/002580246400400404
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Cocaine- and amphetamine-regulated transcript (CART) peptide is a novel neuropeptide involved in feeding, drug reward, and stress. We hypothesized that the polymorphism of CART gene might be related with susceptibility to neuropsychiatric diseases such as alcoholism, bipolar disorder, and schizophrenia. The polymorphism (rs2239670) in intron 1 was selected for study among other single nucleotide polymorphisms (SNPs) located at the area of CART gene, because it had not been tested until to date. The study included patients of alcoholism (100), bipolar disorder (76) and schizophrenia (169) from the Korean population. Healthy controls for bipolar disorder and schizophrenia consisted of 333 individuals. For alcoholism, both patient group and control subjects included only male. The restriction fragment length polymorphism (RFLP) using the AvaII restriction enzyme was designed to analyze the selected SNP. The distribution of GG, GA, and AA genotypes in the 333 controls was 50.2, 41.1, and 8.7%, respectively. The frequency of G and A alleles in the 333 controls was 70.7 and 29.3%, respectively. The distribution of genotype and allele frequencies of the AvaII polymorphism showed a significant difference between alcoholism and controls (P = 0.037 and P = 0.044). However, the AvaII polymorphism of the CART gene did not show association with bipolar disorder and schizophrenia. In conclusion, we report for the first time that the AvaII polymorphism (rs2239670) in intron 1 of the CART gene is associated with alcoholism in the Korean male population.
UNLABELLED: Cigarette smoking is highly destructive to individuals and society, and is moderately heritable. We completed a genomewide linkage scan to map loci increasing risk for cigarette smoking in a set of families originally identified because they segregate panic disorder (PD). One hundred forty two genotyped individuals in a total of 12 families were studied (214 subjects analyzed, including non-genotyped individuals). Of these individuals, 69 were "affected" with habitual cigarette smoking (i.e., they smoked more than one pack per day for at least a year, or at least 1/2 pack per day for at least 10 years), 49 were "unaffected" (i.e., they smoked less than 1/2 pack per day for less than 1 year), and 24 were scored as "unknown." Nine families from the panic series were excluded from these analyses because they lacked multiple affected individuals with habitual cigarette smoking. In an initial genomewide scan, we genotyped a total of 416 markers (398 autosomal, 18 X-chromosome) with an average spacing of less than 10 cM, spanning the genome. Linkage analysis (pairwise, or single-point, and multi-point) was performed using ALLEGRO. An additional 14 markers were genotyped in a high-density panel to follow-up on an identified region of interest on chromosome 11p. The three highest multi-point Zlr scores (3.43, 3.04, and 3.01; P = 0.0003, P = 0.0012, and P = 0.0013, respectively), which each reflect "suggestive" evidence for linkage, were observed in multi-point linkage analyses using Allegro on chromosomes 11p and 9, near markers D11S4046, D9S283, and D9S1677, respectively. D11S4046 is in a region where linkage to alcohol dependence and linkage disequilibrium to substance dependence have previously been identified. The chromosome 9 region we identified as possibly linked to cigarette smoking in anxiety families, was previously identified as significantly linked to PD in Icelandic pedigrees. We also identified evidence supporting linkage (Zlr score > 2.3, P < 0.01) to regions of chromosomes 14, 16, and X. There was a significant phenotypic association between PD and cigarette smoking (P < 0.001). CONCLUSIONS: We identified evidence for two loci increasing risk for cigarette smoking that map to chromosomes 9 and 11. There is now evidence supporting linkage or association of chromosome 11 markers with alcohol dependence, illegal drug abuse and dependence, and cigarette smoking. Interestingly, one of our most promising linkage regions, includes a region previously identified as linked to PD.
Several correlated phenotypes, alcohol dependence, major depressive syndrome, and an endophenotype of electrophysiological measurements, event-related oscillations (EROs), have demonstrated linkage on the long arm of chromosome 7. Recently, we reported both linkage and association between polymorphisms in the gene encoding the muscarinic acetylcholine receptor M2 (CHRM2) and EROs. In this study, we evaluated whether genetic variation in the CHRM2 gene is also a risk factor for the correlated clinical characteristics of alcoholism and depression. The CHRM2 gene contains a single coding exon and a large 5' untranslated region encoded by multiple exons that can be alternatively spliced. Families were recruited through an alcohol dependent proband, and multiplex pedigrees were selected for genetic analyses. We examined 11 single nucleotide polymorphisms (SNPs) spanning the CHRM2 gene in these families. Using the UNPHASED pedigree disequilibrium test (PDTPHASE), three SNPs (one in intron 4 and two in intron 5) showed highly significant association with alcoholism (P=0.004-0.007). Two SNPs (both in intron 4) were significantly associated with major depressive syndrome (P=0.004 and 0.017). Haplotype analyses revealed that the most common haplotype (>40% frequency), T-T-T (rs1824024-rs2061174-rs324650), was under-transmitted to affected individuals with alcohol dependence and major depressive syndrome. Different complementary haplotypes were over-transmitted in alcohol dependent and depressed individuals. These findings provide strong evidence that variants within or close to the CHRM2 locus influence risk for two common psychiatric disorders.