Abstracts: Other Genes

Comings, D.E., Comings, B.G., Muhleman, D., Dietz, G., Shahbahrami, B., Tast, D., Knell, E., Kocsis, P., Baumgarten, R., Kovacs, B.W., Levy, D.L., Smith, M., Kane, J.M., Lieberman, J.A., Klein, D.N., MacMurray, J., Tosk, J., Sverd, J., Gysin, R., & Comings, D.E., Muhleman, D., Dietz, G., Sherman, M., & Forest, G. (1995). Sequence of human tryptophan 2,3-dioxygenase: Presence of a glucocorticoid response-like element composed of a GTT repeat and an intronic CCCCT repeat. Genomics, 29: 390-396.
      Defects in serotonin metabolism, and abnormalities in both blood serotonin and tryptophan levels, have been reported in many psychiatric disorders. Tryptophan 2,3-dioxygenase (TDO2) is the rate limiting enzyme for the breakdown of tryptophan to N-formyl kenurenine. Functional variants of this gene could account for the observed simultaneous increases or decreases of both serotonin and tryptophan in various disorders. We have identified four different polymorphisms of the human TDO2 gene. Association studies show a significant association of one or more of these poylmorphisms with Tourette syndrome (TS), attention deficit hyperactivity disorder (ADHD) and drug dependence. The intron 6G->T variant was significantly associated with platelet serotonin levels. While only the association with TS was significant with a Bonferroni correction, we hope these preliminary results serve to stimulate further studies of the potential role of the TDO2 gene in a range of psychiatric disorders.

Comings, D.E., Wu, J., Chiu, C., Muhleman, D., & Sverd, J. (1996). Studies of c-Harvey-Ras gene in psychiatric disorders. Psychiatry Res., 63: 25-32.
      Herault et al. (1993) previously reported a significant association between autism and the larger fragments of the c-Harvey-Ras (HRAS) Bam H1 polymorphism. We have sought to verify this finding and determine if there was any evidence for an association with other psychiatric disorders. Because of its greater sensitivity, we have examined the HRAS Msp 1 polymorphism. We found a just significant increase in the prevalence of the > 2.1 kb alleles in 48 subjects with autism versus 50 control subjects. There was no increase in the prevalence of the > 2.1 kb alleles in 164 probands with Tourette's syndrome. Examination of 16 preselected symptom clusters, however, showed a significant trend toward higher scores for obsessive- compulsive and phobic symptoms in > 2.1 kb homozygotes. While this locus requires further study, in conjunction with the results of Herault et al., the present findings suggest that genetic defects in HRAS, and possibly other components of the G protein secondary messenger system, may play a role in some psychiatric disorders.

Comings, D.E., Muhleman, D., Gade, R., Chiu, C., Wu, H., Dietz, G., Winn-Dean, E., Ferry, L., Rosenthal, R.J., Lesieur, H.R., Rugle, L., Sverd, J., Johnson, P., & MacMurray, J.P. (1996). Exon and intron mutations in the human tryptophan 2,3-dioxygenase gene and their potential association with Tourette syndrome, substance abuse and other psychiatric disorders.  Pharmacogenetics, 6: 307-318.
      Defects in serotonin metabolism, and abnormalities in both blood serotonin and tryptophan levels, have been reported in many psychiatric disorders. Tryptophan 2,3-dioxygenase (TDO2) is the rate limiting enzyme for the breakdown of tryptophan to N-formyl kenurenine. Mutations of this gene could account for the observed simultaneous increases or decreases of both serotonin and tryptophan in various disorders. We have identified four different polymorphisms of the human TDO2 gene. Association studies with over 900 subjects have shown a significant association of one or more of these poylmorphisms with Tourette syndrome (TS), attention deficit hyperactivity disorder (ADHD) and drug dependence. The intron 6G->T mutation was associated with a significant change in platelet serotonin level. These associations are consistent with the hypothesis that these disorders are inherited in a polygenic fashion, that the TDO2 gene is contributing to a portion of the phenotype, and that these and related disorders are due, in part, to mutations that disturb serotonin metabolism.

Comings DE, Gonzalez N,Wu S, Gade R, Muhleman,D, Saucier G, Johnson P,Verde R, Rosenthal RJ, Lesieur HR, Rugle LJ, Miller WR, MacMurray JP. (1999) Studies of the 48 bp repeat of the DRD4 gene in impulsive-addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse. Am. J. Med. Gen. (Neuropsych.Genet.) 88:358-368.
      Prior studies have reported an association between the presence of the 7 repeat allele of the 48 bp repeat polymorphism of the third cytoplasmic loop of the dopamine D4 receptor gene (DRD4) and novelty seeking behaviors, ADHD, Tourette syndrome, pathological gambling, and substance abuse. However, other studies have failed to replicate some of these observations. To determine if we could replicate these associations we genotyped 737 individuals from four different groups of control subjects, and 707 index subjects from four different groups of impulsive, compulsive addictive behaviors including substance abuse, pathological gambling, Tourette syndrome (TS), and ADHD. Chi square analysis of those carrying the 7 allele versus non-7 allele carriers were not significant for any of the groups using a Bonferroni corrected a of .0125. However, chi square analysis of those carrying any 5 to 8 allele versus non-carriers was significant for pathological gambling (p < .0001), ADHD (p = .01) and the total index group (p ¥= .0004). When the comparison included all 7 alleles the results were significant for gamblers (p < .0001), Tourette syndrome (p ¥= .003), ADHD (p = .003) and the total group (p = .0002). There was a significant increase in the frequency of heterozygosity versus homozygosity for all alleles for pathological gamblers (p ¥= .0031) and the total index group (p = .0015), suggesting that heterosis played a role. In the substance abuse subjects a quantitative summary variable for the severity of drug dependence, based on the Addiction Severity Index, showed that the scores varied by increasing severity across the following genotypes: 44 < heterozygotes < 77 < 22. Studies of other quantitative traits indicated an important role for the 2 allele and the 22, 24 and 27 genotypes. All studies indicated that the role of the DRD4gene in impulsive, compulsive, addictive behaviors is more complex than a sole focus on the 7 versus non-7 alleles.

Johnson, J.P., Muhleman, D., MacMurray, J., Gade, R., Verde, R., Ask, M., Kelley, J., & Comings, D.E. (1997). Association between the cannabinoid receptor gene (CNR1), and the P300 wave of event-related potentials, and drug dependence. Molecular Psychiatry, 2 : 169-171.
       In our prior study we observed a significant association between homozygosity for the "5 alleles of a microsatellite polymorphism of cannabinoid receptor gene (CNR1) and drug dependence. Decreased amplitude of the P300 wave of evoked related potentials (ERP) has long been shown to be associated with alcohol and drug dependence. The P300 wave reflects attentional resource allocation and active working memory. Since marijuana intoxication has a potent blocking effect on short term memory we examined the association between the CNR1 alleles and the P300 wave amplitude at three electrodes in 35 alcohol and drug addicts, by MANOVA. There was a significant decrease in amplitude of the P300 wave for all three electrodes (p = .028) that was most marked for the frontal lobes (p = .008) in subjects homozygous for the CNR1 "5 repeat alleles. Multivariate regression analysis indicated the CNR1 gene contributed to 20 percent of the variance of the frontal lobe P300 wave amplitude.

Comings, D.E., Gade, R., Wu, S., Chiu, C., Dietz, G., Muhleman, D., Saucier, G., Ferry, L., Burchete, R., Johnson, P., Verde, R., & MacMurray, J.P. (1997).  Studies of the potential role of the dopamine D1 receptor gene in addictive behaviors. Molecular Psychiatry, 2: 44-56.
       Abnormalities in the dopaminergic reward pathways have frequently been implicated in substance abuse and addictive behaviors. Recent studies by Self and coworkers have suggested an important interaction between the dopamine D1 and D2 receptors in cocaine abuse. To test the hypothesis that the DRD1 gene might play a role in addictive behaviors we examined the alleles of the Dde I polymorphism in three independent groups of subjects with varying types of compulsive, addictive behaviors - Tourette syndrome probands, smokers and pathological gamblers. In all three groups there was a significant increase in the frequency of homozygosity for the DRD1 Dde I 1 or 2 alleles in subjects with addictive behaviors. The DRD1 11 or 22 genotype was present in 41.3% of 63 controls and 57.3% of 227 TS probands (p = .024). When 23 quantitative traits were examined by ANOVA those carrying the 11 genotype consistently had the highest scores. Based on these results, we examined the percentage of controls, TS probands without the specific behavior, and TS probands with the specific behavior. There was a progressive, linear increase, significant at a *.005, for scores for problems with gambling, alcohol use and compulsive shopping. Problems with three additional behaviors, drug use, compulsive eating and smoking were significant at a *.05. All 6 variables were related to addictive behaviors. In a totally separate group of controls and individuals attending a smoking cessation clinic, and smoking at least one pack per day, 39.3% of the controls versus 66.1% of the smokers carried the 11 or 22 genotype (p = .0002). In a third independent group ofpathological gamblers, 55.8% carried the 11 or 22 genotype (p = .009 versus the combined controls). In the TS group and smokers there was an additive effect of the DRD1 and DRD2 genes. The results for both the DRD1 and DRD2 gene, which have opposing effects on cyclic AMP, were consistent with negative and positive heterosis, respectively. These results support a role for genetic variants of the DRD1 gene in some addictive behaviors, and an interaction of genetic variants at the DRD1 and DRD2 genes.

Comings, D.E., Muhleman, D., Gade, R., Johnson, P., Verde, R., Saucier, G., & MacMurray, J. (1997). Cannabinoid receptor gene (CNR1): Association with IV drug use. Molecular Psychiatry, 2: 161-168.
      The receptors for tetrahydrocannabinol, the active ingredient of marijuana, have been identified. A microstatellite polymorphism (AAT)n at the cannabinoid CB1 (brain) receptor gene (CNR1) consists of 9 alleles. Since the cannabinoid system is part of the reward pathway we examined the hypothesis that genetic variants of the CNR1 gene might be associated with susceptibility to alcohol or drug dependence. The study consisted of 92 subjects on an Addiction Treatment Unit (ATU) and 114 controls. All were non-Hispanic Caucasians. The ATU subjects were screened for all types of substance dependence using the Diagnostic Interview Schedule (DIS), and for a variety of substance abuse symptoms using the Addiction Severity Index (ASI). Since inspection of the distribution of alleles in controls versus IV drug use showed a decrease in the frequency of the 4 allele, and the <4 alleles were rare, the alleles were divided into two groups, <5 and '5, and three genotypes <5/<5, heterozygotes, and '5/'5. When all variables were subjected to factor analysis, factor 1 showed a clustering of drug dependence variables and factor 2 of alcohol dependence variables. By ANOVA only factor 1 showed significant differences by genotype consistent with a model where homozygosity for the '5 repeat alleles showed the greatest effect. The number of drugs used IV was significantly greater for those carrying the '5/'5 genotype than other genotypes (p = .005). The association with specific types of drug dependence was greatest for cocaine, amphetamine, and cannabis dependence. The results are consistent with a role of cannabinoid receptors in the modulation of dopamine and cannabinoid reward pathways.

Gade, R., Muhlemann, D., MacMurray, J., & Comings, D.E. (1998). Correlation of length of VNTR alleles at the X-linked MAOA gene and phenotypic effect in Tourette syndrome and drug abuse. Molecular Psychiatry, 3: 50-60.
         Abnormalities in monoamine oxidase (MAO) levels have been implicated in a wide range of psychiatric disorders. We have examined a VNTR polymorphism at the X-linked MAOA gene to test two hypotheses: 1. Do variants of the MAOA gene play a role in any of the behavioral disorders associated with Tourette syndrome or drug abuse? 2. If so, is there any correlation between the length of the alleles and the phenotypic effect? We examined two independent groups: 375 TS patients, relatives and controls, and 280 substance abusers and controls. The alleles were divided into four groups of increasing size. There was a significant association between the MAOA gene and behavioral phenotypes in both groups, and in both the longest alleles were associated with the greatest phenotypic effect. The strongest effect was for the diagnosis of drug dependence (p = .00003). The VNTR allele groups were in significant linkage disequilibrium with the Fnu4H1 polymorphism previously shown to be associated with MAO-A activity. While these results are consistent with the possibility that different sized alleles of the short-repeat polymorphisms themselves may play a role in gene regulation, further studies directly linking these alleles with enzyme levels need to be done.

Comings, D.E., Blake, H., Dietz, G., Gade-Andavolu, R., Legro, R., Saucier, G., Johnson, P., Verde, R., & MacMurray, J.P. (1999). The proenkephalin gene (PENK) and opioid dependence.  NeuroReport, 10: 1133-1135.
We tested the hypothesis that the alleles at the (CA)n repeat of the proenkephalin gene (PENK) might be associated with opioid addiction in 31 non-Hispanic Caucasian subjects with opioid dependence (heroin), 89 ethnically matched subjects with substance dependence other than opioid dependence, and 132 controls. In the subjects with opioid dependence, 66% carried the 81 bp allele compared to 40 percent of subjects with other types of substance abuse (c2 = 11.31, p < .004), and 49% of controls (c2 = 6.0, p < .015). These results are consistent with a role of the PENK gene in opioid dependence.

Comings DE, MacMurray JP, Gonzalez N, Ferry L, Peters,WR. (1999). Association of the serotonin transporter gene with serum cholesterol levels and heart disease. Molecular Genetics and Metabolism 67:248-253.
      Background In a study of a group of elderly athletes we observed an unexpected association between serum cholesterol levels and the HTTLPR insertion /deletion polymorphism of the promoter region of the serotonin transporter gene ( HTT, SLC6A4). As a follow-up we examined the potential association of this polymorphism with cholesterol and triglyceride levels, or heart disease, in two other groups of subjects.
      Methods We examined the possible association between cholesterol levels and heart disease and genotypes of the HTTLPR insertion /deletion polymorphism of the promoter region of the HTTgene, in three independent study populations ranging from 42 to 90 years of age.
     Results For subjects 55 to 70 years of age in group 1, cholesterol levels were significantly greater in the LS heterozygotes than either LL or SS homozygotes indicating a heterosis effect (p ¥= .0001). This was replicated in group 2 (p ¥= .015). Triglyceride levels were also significantly elevated in the LS subjects (p ¥= .002). In groups 1 and 3 there was a significant association between the LS heterozygosity and heart disease, angina, and heart attacks in subjects 70 years of age or less. All of these associations were absent in subjects > 70 years of age.
      Conclusion While these studies are preliminary and exploratory, they are consistent with a relationship of the HTTgene to cholesterol levels and a risk for heart disease. Replication of these findings in independent, epidemiologically based studies is required.

Comings,D.E., Dietz.G.., Johnson,J.P., MacMurray,J.P.(1999) Association of the enkephalinase gene with low amplitude P300 waves. Neuroreport 10:2283-2285.
       Low amplitude of the P300 evoked potential waves has been linked to substance abuse. Defects in opioidergic genes regulating reward pathways have been implicated as risk factors in substance abuse. Since the rate of degradation of enkephalins regulates their CNS level, we focused on the MME gene for metalomembrane endopeptidase (neutral endopeptidase, enkephalinase). We identified a GT repeat polymorphism 5' to the gene and examined its potential association with P300 wave amplitude in 25 male subjects with substance abuse. There was significant association of low molecular weight alleles with low amplitude of the P300 wave at the parietal (p = .0087) and coronal (p = .009) leads. These results support a role of endogenous opioids in the regulation of P300 wave amplitude.

Comings, D. E., N. Gonzalez, S. Wu, G. Saucier, P. Johnson, R. Verde, and J. P. MacMurray. (1999). Association of the Dopamine DRD3 Receptor Gene With Cocaine Dependence. Molecular Psychiatry 4:484-87.
       We examined the hypothesis that the dopamine D3 receptor gene (DRD3) is a susceptibility factor for cocaine dependence. The Msc I/Bal I polymorphism of the DRD3 gene was examined in 47 Caucasian subjects with cocaine dependence and 305 Caucasian controls. Based on prior studies with a range of psychiatric disorders we hypothesized there would be a decrease in the frequency of the 12 genotype in the patient sample (increased homozygosity). We observed a significant decrease in the frequency of 12 heterozygotes in subjects with cocaine dependence (29.8%) versus controls (46.9%) (p ¥= .028). This percentage was still lower in those had who chronically used cocaine for more than 10 years (25%), or more than 15 years (21.5%). There was not a significant decrease in DRD3 12 heterozygosity for subjects with amphetamine, opioid, or alcohol dependence in the absence of cocaine dependence. The DRD3 gene accounted for 1.5% of the variance of cocaine dependence (p ¥= .02). The DRD2 gene had an independent and additive effect on cocaine dependence. These findings support a role of the DRD3 gene in susceptibility to cocaine dependence.

Comings, D. E., D. Muhleman, P. Johnson, and J. P. MacMurray. (1999). Potential Role of the Estrogen Receptor Gene (ESR1) in Anxiety. Molecular Psychiatry 4:374-77.
      In addition to neurotransmitters, hormones, acting through the blood stream, also play a role in behavior. To test the potential contribution of genetic variations in hormone receptors we have examined the association between the alleles of the dinucleotide repeat of the estrogen receptor 1 gene (ESR1) and the 9 subscores and total score of the SCL-90 in a group of 179 adult males treated for substance abuse. Based on our prior hypothesis that the length of repeat polymorphisms may play a direct role in gene regulation, the alleles were divided into two groups, short (S) and long (L). ANOVA of the SS, LS, and LL genotypes showed a significant association at ¥= .05 for three of the SCL-90 scores: anxiety, phobic anxiety, and Total Symptoms. Of these the anxiety score remained significant at a Bonferroni corrected of ¥= .005. By regression analysis, the ESR1 gene accounted for 7 percent of the variance of the anxiety score (p ¥= .0004). These results are consistent with a role of the ESR1 gene in human behavior. Since estrogen levels are much higher in women than men, this could account for the increased frequency of anxiety in women.

Winsberg, B. and D. Comings. (1999).  Association of the Dopamine Transporter Gene (DAT1) With Poor Methylphenidate Response. J.Am.Acad.Child.Adolesc.Psychiatry 38:1474-77.
      Poor Ritalin response in African American boys with ADHD was associated with homozygosity at the 10 allele of the dopamine transporter gene.

Comings,D.E., Johnson,J.P., Gonzalez,N.S., Huss,M., Saucier,G. and MacMurray,J. (2000) Association between the adrenergic a2A receptor gene (ADRA2A) and measures of irritability, hostility, impulsivity and memory in normal subjects: A study and a replication. Psychaitric Genetics 55: 160-172.
      The noradrenergic system has been implicated in arousal, vigilance, irritability hostility, and memory. This suggests the hypothesis that genetic variants at noradrenergic receptors may be risk factors of these behaviors. To test this we examined the potential association between measures of these traits and genetic variation at the adrenergic2A receptor gene (ADRA2A) , using  a common  SNP polymorphism of the promoter region, in two independent sets of subjects: university students (student group) and parents of twins in the Minnesota Twin Study (twin group). In the student group there was a significant linear association by genotype (11 > 12 > 22) for the total Brown ADD score (BADD)  and BADD subscores of memory and irritability, and with the total Buss-Durkey Hostility Inventory (BDHI) score and BDHI subscores of indirect hostility, irritability, negativity,  and verbal aggression. A MANOVA  of all the BADD and BDHI subscores was significant at p ¥ .009. For the twins group the same genotype associations were significant for the Multidimensional Personality Questionnaire impulsivity scores but not for the MPQ aggression or harm avoidance scores. The ADRA2A gene accounted for 1.8 to 8.3 percent of the variance of these scores.

Comings, D.E. and MacMurray, J.P. (2000). Molecular Heterosis: A Review. Molecular Genetics and Metabolism. 71:19-31.
        Molecular heterosis occurs when subjects heterozygous for a specific genetic polymorphism show a significantly greater effect (positive heterosis) or lesser effect (negative heterosis) for a quantitative or dichotomous trait than subjects homozygous for either allele. At a molecular level heterosis appears counter-intuitive to the expectation that if the 1 allele of a two allele polymorphism is associated a decrease in gene expression, those carrying the 11 genotype should show the greatest effect, 12 heterozygotes should be intermediate, and 22 homozygotes should show the least effect. We review the accumulating evidence that molecular heterosis is common in humans and may occur in up to fifty percent of all gene associations. A number of examples are reviewed including the following genes: ADRA2C, C3 complement, DRD1, DRD2, DRD3, DRD4, ESR1, HP, HBB, HLA-DR DQ, HTR2A, properdin B, SLC6A4, PNMT, and secretor.Several examples are given in which the heterosis is gender specific. Three explanations for molecular heterosis are proposed. The first is based on an inverted U shaped response curve in which either to little or too much gene expression is deleterious with optimal gene expression occurring in 12 heterozygotes. The second, proposes an independent third factor causing a hidden stratification of the sample such that for in one set of subjects 11 homozygosity is associated with the highest phenotype score while in the other set, 22 homozygosity is associated with the highest phenotype score. The third explanation suggests greater fitness in 12 heterozygotes because they show a broader range of gene expression than 11 or 22 homozygotes. Allele based linkage techniques usually miss heterotic associations. Because up to 50 percent of association studies show a heterosis effect, this can significantly diminish the power of family based linkage and association studies.

Comings,D.E., Dietz,G., GadeAndavolu,R., Blake,H., Muhleman,D., Huss,M., Saucier,G. and MacMurray,J.P.  (2000) Association of the neutral endopepdidase (MME) gene with anxiety. Pyschiatric Genetics. 10: 91-94. 
       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 metabolismin anxiety.

Comings,D.E., Muhleman,D., Wu,S. and MacMurray,J.P. (2000). Association of the N-a-acetyltransferase gene (NAT1) with mild and severe substance abuse. NeuroReport 11:1227-1230.
      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.

Comings DE, Gonzales N, Saucier G, Johnson JP,  MacMurray JP. (2000) The DRD4 gene and the spiritual transcendence scale of the character temperament index. Psychiatry Genet 10:185-189
      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. (2000). Serotonin transporter gene polymorphisms in alcohol dependence. Alcohol 22:61-7
       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. (2001) Phenylethanolamine N-methyltransferase (PNMT) gene and early-onset Alzheimer disease. Am J Med Genet 105:312-6.
       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 DE, Wu S, Rostamkhani M, McGue M, Iacono WG, MacMurray JP. (2002). Association of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in women. Am J Med Genet 114:527-9
       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 r2 =.030, F = 13.37, P =.0003. By contrast, in men r2 =.00001, F = 0.002, P =.96. These results are consistent with a gender-specific role of the CHRM2 gene in depression in women.