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P#91 - P#100
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: Comings,D.E., Dietz,G., GadeAndavolu,R., Blake,H., Muhleman,D., Huss,M., Saucier,G. and MacMurray,J.P. Association of the neutral endopepdidase (MME) gene with anxiety Psychiatric Genetics. 10: 91-94, 2000ABSTRACT:
Enkephalins have been implicated in the regulation of mood, anxiety, reward, euphoria and pain. One of the major enzymes for enkephalin degradation is neutral endopeptidase (enkephalinase, membrane metalloendopeptidase, MME). We identified a dinucleotide polymorphism in the 5'-region of the MME gene. Subjects were placed into three genotypes, 3/3, 3/x, and x/x since the 3 allele was the most common of the 6 alleles. Using one-way ANOVA we examined the association of these genotypes with the mean SCL-90 scores for anxiety, depression, obsessive-compulsive and phobic anxiety symptoms in 120 Caucasian males from an addiction treatment unit. There was a significant association between the MME genotypes and the SCL-90 scores for phobic anxiety, obsessive-compulsive and anxiety at a Bonferroni corrected a of .0125. These results support a role of genetic variants of enkephalin metabolism in anxiety.
: Comings,D.E., Muhleman,D., Wu,S. and MacMurray,J.P. Association of the N-a-acetyltransferase gene (NAT1) with mild and severe substance abuse NeuroReport 11:1227-1230, 2000ABSTRACT:
We observed a significant increase in the number subjects carrying the NAT1*10 allele of the N-acetyl transferase1 (NAT1) gene in controls with a MAST-R score of 4 or more, and in subjects with drug and/or alcohol dependence (p ¥ .003), compared to controls with a MAST-R of less than 4. These results suggest that alterations in the acetylation of one or more CNS compounds may be related to both mild and severe substance abuse.
: Madrid GA, MacMurray J, Lee JW, Anderson BA, Comings DE. Stress as a mediating factor in the association between the DRD2 TaqI polymorphism and alcoholism School of Public Health, Loma Linda University, 11201 Benton St., Loma Linda, CA 92357, USA. Alcohol 2001 Feb;23(2):117-22ABSTRACT:
Results of earlier studies have shown that rating of prior stress exposure in preadolescent boys influenced the association between DRD2 genotypes and alcoholism risk factors, suggesting that variability in stress exposure, either in patient or control samples, could readily account for at least part of the confusion in DRD2 study outcomes. In order to test the hypothesis that the DRD2 A1 allele is only associated with alcoholism in subjects with elevated stress exposure, we examined the gene-stress interactional model in a sample of males of Mayan descent in the Olancho district of Honduras. Ascertainment was based on an epidemiologic, observational cross-sectional design, and the study was approved by the Institutional Review Board. A total of 309 adult males (age range 18-87 years) were interviewed by a physician or a public health nurse, blood samples were obtained for genetic studies, and participants were administered the short version of the Michigan Alcoholism Screening Test (S-MAST) and the Hispanic Stress Inventory (HSI). Three explanatory models were evaluated. The first model tested the effect of the demographic variables alone as predictors of MAST scores, the second tested the effects of stress and DRD2 genotypes separately, and the third tested the effect of the interaction between stress and the DRD2 genotypes. Neither model 1 nor model 2 yielded significant results; neither MAST scores nor HSI scores were found to be associated with DRD2 genotypes. However, Model 3 was confirmed reflecting a significant (P<.05) interaction between DRD2 genotype and stress score as a predictor of MAST score. Additionally, this difference was found to be largely accounted by the HSI occupational/economic stress score, which had a highly significant (P=.003) interaction with DRD2 genotype as a predictor of MAST score. This stress score was the only one of four that showed levels of stress as high as HSI scores in a US population. The MAST scores of A2A2 genotype participants were found to be nearly identical in low stress and high stress participants, whereas the MAST scores of A1A2 participants increased modestly with stress (P=.01) and that of A1A1 participants increased markedly with stress (P=.001). These findings support the hypothesis that DRD2 genotype-phenotype associations depend on the magnitude of stress exposure, and they lend support to the view that variability in DRD2 study outcomes may in part be explained by this gene-environment interaction.
: Comings DE, Gonzales N, Saucier G, Johnson JP, MacMurray JP. The DRD4 gene and the spiritual transcendence scale of the character temperament index Psychiatry Genet 2000 Dec;10(4):185-9ABSTRACT:
Two hundred male subjects (81 college students and 119 subjects from an addiction treatment unit) were administered the Temperament and Character Inventory (TCI) and genotyped at the 48 base pair repeat polymorphism of the DRD4 gene. Subjects were divided by genotype into those carrying any 4 repeat allele, those homozygous for the 4 repeat allele, and those with any 4 repeat allele. The total MANCOVA of seven TCI summary scores, with age and diagnostic group as covariates, was significant (P < or = 0.001). The largest effect was with self-transcendence (P < or = 0.001). The total MANCOVA for the three self-transcendence subscores was significant (P < or = 0.017), with the spiritual acceptance subscore showing the most effect (P < or = 0.001, power = 0.91). These results suggest the DRD4 gene may play a role in the personality trait of spiritual acceptance. This may be a function of the high concentration of the dopamine D4 receptor in the cortical areas, especially the frontal cortex.
: Thompson MD, Gonzalez N, Nguyen T, Comings DE, George SR, O'Dowd BF. Serotonin transporter gene polymorphisms in alcohol dependence Alcohol 2000 Oct;22(2):61-7ABSTRACT:
The serotonin transporter (5-HTT) gene is a candidate gene in alcohol dependence because serotonin reuptake inhibitors (SRIs) can alleviate alcohol withdrawal. Studies of the 5-HTT gene in alcohol dependence have not resulted in a consensus. Recent studies have examined the transcriptionally active promoter polymorphism, a 44-bp deletion resulting in short (S) or long (L) alleles. In this study, 131 alcohol-dependent patients of Northern and Western European descent were genotyped. Seventy of these patients were diagnosed with alcohol dependence without comorbid disorders. Sixty-one patients were diagnosed with alcohol dependence comorbid with Tourette syndrome (alcoholic-TS). We found an excess of the S allele in alcohol-dependent patients (47%) compared with 125 ethnically matched controls (39%). A similar trend was found in 150 ethnically matched TS patients without alcohol dependence comorbidity (51%). However, the statistical significance of this trend in the data was not present after Bonferroni correction. The data presented suggests a trend toward increased frequency of the S promoter allele in alcohol-dependent, alcoholic-TS and TS patients.
: Mann MB, Wu S, Rostamkhani M, Tourtellotte W, MacMurray J, Comings DE. Phenylethanolamine N-methyltransferase (PNMT) gene and early-onset Alzheimer disease Am J Med Genet 2001 May 8;105(4):312-6ABSTRACT:
The activity of human phenylethanolamine N-methyltransferase (PNMT) is reduced in the neurons of those cells in many subcortical areas of the brain that are known to undergo neurodegeneration in Alzheimer disease (AD). Others have reported that PNMT is decreased in brains of persons with AD and that the decrease in enzymatic activity is due to a reduced amount of the enzyme protein. We have previously described two polymorphisms, G-353A and G-148A, in the promoter region of the gene coding for PNMT. These markers were tested for their association with the occurrence of sporadic AD. Genotyping of 131 necropsy confirmed AD cases, and 947 adult nondemented controls were completed. We observed a significant association between both of the PNMT gene polymorphisms and early-onset AD (EOAD) (P </= 0.007), but not in late-onset AD (LOAD). These data suggest that genetic variation in the promoter of the PNMT gene is associated with increased susceptibility to the sporadic form of EOAD. Copyright 2001 Wiley-Liss, Inc.
: Comings, D.E. Clinical and Molecular Genetics of ADHD and Tourette Syndrome: Two Related Polygenic Disorders Ann. N.Y. Acad. Sci. 931: 50-83, 2001ABSTRACT:
ADHD is a polygenic disorder due to the additive effect of genes affecting dopamine, norepinephrine, serotonin, GABA, and other neurotransmitters. Some of the specific loci involved are dopamine genes - DRD2, DRD4, DRD5, and the dopamine transporter; norepinephrine (NE) and epinephrine (EPI) genes - dopamine __hydroxylase, ADRA2A, ADRA2C, PNMT, norepinephrine transporter, MAOA, COMT; serotonin genes - TDO2, HTR1A, HTR1DA, serotonin transporter; GABA genes - GABRB3; androgen receptor and other genes. This model is consistent with the all of the present knowledge about ADHD including a) the increased frequency of ADHD in the relatives of ADHD probands, b) the presence of a wide spectrum of comorbid behaviors (depression, anxiety, learning, conduct, oppositional-defiant, conduct and substance abuse disorders) in ADHD probands and their relatives on both parental sides, c) the close relationship to Tourette syndrome (TS), d) the failure to find the genes for TS using linkage analysis, e) the brain imaging studies showing hypometabolism of the frontal lobes, f) the relationship between dopamine D2 receptor density and regional blood flow, g) the correlation between tics and dopamine D2 receptor density in TS, h) the motor hyperactivity of dopamine transporter and dopamine D3 receptor gene knockout mice, i) the LeMoal and Shaywitz dopamine deficiency animal models of ADHD, j) the NE models of ADHD, k) the failure to explain ADHD on the basis of any single neurotransmitter defect, l) the response of ADHD to dopamine and _2-adrenergic agonists, m) the small percentage of the variance of specific behaviors accounted for by each gene, and numerous other aspects of ADHD. The implications of the polygenic model for the understanding, diagnosis and treatment of ADHD and TS, as well as other psychiatric disorders, are reviewed.
: Comings DE, Muhleman D, Johnson JP, MacMurray JP. Parent-daughter transmission of the androgen receptor gene as an explanation of the effect of father absence on age of menarche Child Dev 2002 Jul-Aug;73(4):1046-51ABSTRACT:
Based on an evolutionary theory of socialization, Belsky and colleagues proposed that girls exposed to a stressful environment, especially when due to father absence in the first 7 years of life, showed an early onset of puberty, precocious sexuality, and unstable relationships as adults. The authors of this article examined an alternative explanation that a variant X-linked androgen receptor (AR) gene, predisposing the father to behaviors that include family abandonment, may be passed to their daughters causing early puberty, precocious sexuality, and behavior problems. The results of a study of 121 White males and 164 White females showed a significant association of the short alleles of the GGC repeat polymorphism of the AR gene with a range of measures of aggression and impulsivity, increased number of sexual partners, sexual compulsivity, and lifetime number of sex partners in males; and paternal divorce, father absence, and early age of menarche in females. These findings support a genetic explanation of the Belsky psychosocial evolutionary hypothesis regarding the association of fathers' absence and parental stress with early age of onset of menarche and early sexual activity in their daughters. A genetic explanation of the father absence effect is proposed in which fathers carrying the AR alleles are more likely to abandon a marriage (father absence) and pass those alleles to their daughters in whom they produce an earlier age of menarche and behavioral problems.
: Comings DE, Wu S, Rostamkhani M, McGue M, Iacono WG, MacMurray JP. Association of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in women Am J Med Genet 2002 Jul 8;114(5):527-9ABSTRACT:
Cholinergic neurons have been implicated in depression and in the disorders of REM sleep in depression. We examined a common A-> T 1890 polymorphism in the 3' UTR of the cholinergic muscarinic receptor 2 (CHRM2) gene. There was a significant increase in the frequency of 11 homozygotes in 126 women with major depression (43.7%) compared to 304 women without major depression (25.7%), P =.001. There was no increase in the frequency of 11 homozygotes in 52 men with depression (26.9%) compared to 278 men without depression (27.7%). Regression analysis, scoring subjects with the 11 genotype as 1, and those with other genotypes as 0, showed that in women r(2) =.030, F = 13.37, P =.0003. By contrast, in men r(2) =.00001, F = 0.002, P =.96. These results are consistent with a gender-specific role of the CHRM2 gene in depression in women. Copyright 2002 Wiley-Liss, Inc.