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Mary-Anne Enoch

Publications and source records attributed to Mary-Anne Enoch.

16 recordsLinked to original sources
PubMed2006

Association of THR105Ile, a functional polymorphism of histamine N-methyltransferase (HNMT), with alcoholism in German Caucasians.

BACKGROUND: CNS histamine has been shown to have an inhibitory effect on reward and it is implicated in the etiology of addiction and stress. Histamine N-methyltransferase (HNMT) is believed to be the sole pathway for termination of the neurotransmitter action of histamine in mammalian brain. A common, functional polymorphism, a C314T transition in the HNMT gene, results in a Thr105Ile substitution of the protein encoded. A recent study has shown that the frequency of the Ile105 allele was significantly lower in alcoholics compared to that in non-alcoholics in Finns and Plains American Indians. Following up these results, we tested whether the Thr105Ile polymorphism was associated with alcoholism in German Caucasians. METHODS: Thr105Ile was genotyped in n=366 psychiatrically interviewed German Caucasian ICD-10 lifetime alcoholics, along with n=200 ethnically matched controls. RESULTS: No significant difference was found in the frequency of the Ile105 allele between alcoholics (0.11) and controls (0.10) (chi(2)=0.21, d.f.=1, p=0.647). Likewise, genotype distributions did not differ significantly. However, the frequency of the Ile105 allele was significantly lower in male alcoholics with a family history of alcoholism compared to that in male alcoholics without a family history of alcoholism (chi(2)=4.07, d.f.=1, p=0.044). CONCLUSIONS: In German Caucasians the association of the HNMT Thr105Ile polymorphism with alcoholism was not replicated per se, but a congruent association was found between the Ile105 allele and family history of alcoholism supporting the protective role of the Ile105 allele against alcoholism.

Adult↗
PubMed2006

Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism.

The GABAAalpha2 receptor gene (GABRA2) modulates anxiety and stress response. Three recent association studies implicate GABRA2 in alcoholism, however in these papers both common, opposite-configuration haplotypes in the region distal to intron3 predict risk. We have now replicated the GABRA2 association with alcoholism in 331 Plains Indian men and women and 461 Finnish Caucasian men. Using a dimensional measure of anxiety, harm avoidance (HA), we also found that the association with alcoholism is mediated, or moderated, by anxiety. Nine SNPs were genotyped revealing two haplotype blocks. Within the previously implicated block 2 region, we identified the two common, opposite-configuration risk haplotypes, A and B. Their frequencies differed markedly in Finns and Plains Indians. In both populations, most block 2 SNPs were significantly associated with alcoholism. The associations were due to increased frequencies of both homozygotes in alcoholics, indicating the possibility of alcoholic subtypes with opposite genotypes. Congruently, there was no significant haplotype association. Using HA as an indicator variable for anxiety, we found haplotype linkage to alcoholism with high and low dimensional anxiety, and to HA itself, in both populations. High HA alcoholics had the highest frequency of the more abundant haplotype (A in Finns, B in Plains Indians); low HA alcoholics had the highest frequency of the less abundant haplotype (B in Finns, A in Plains Indians) (Finns: P = 0.007, OR = 2.1, Plains Indians: P = 0.040, OR = 1.9). Non-alcoholics had intermediate frequencies. Our results suggest that within the distal GABRA2 region is a functional locus or loci that may differ between populations but that alters risk for alcoholism via the mediating action of anxiety.

Adult↗
PubMed2006

Sex differences in the influence of COMT Val158Met on alcoholism and smoking in plains American Indians.

BACKGROUND: Alcoholism and heavy smoking are highly comorbid and are cotransmitted in the general U.S. population; however little is known about comorbidity in American Indians. The catechol-O-methyltransferase (COMT) functional polymorphism, Val158Met, has been associated with alcoholism in Caucasians. The aims of our study were firstly to investigate patterns of alcohol and tobacco consumption and comorbidity between alcoholism and smoking in Plains American Indians and secondly to determine the influence, including sexual dimorphic effects, of COMT Val158Met and COMT haplotypes, on these behaviors. METHODS: Diagnostic and Statistical Manual-III-R lifetime diagnoses were assigned to 342 community-ascertained Plains American Indians (201 women, 141 men). Lifetime drinking and smoking histories were obtained. Five COMT loci, including Val158Met, were genotyped. Haplotype-based analyses identified 1 block with 3 common haplotypes; 2 included Val158, and 1 had the Met158 allele. RESULTS: The alcoholics drank heavily (12+/-8 drinks/drinking day) but episodically (max 10+/-8 d/mo). Although 62% of male alcoholics and 40% of female alcoholics were smokers (> or =10 cigarettes/d), only 12% of alcoholic men and 8% of alcoholic women smoked heavily (>20/d). In women, the COMT Val158 allele frequency was maximal in alcoholic smokers (0.85), decreasing to 0.74 in nonalcoholic smokers, 0.67 in alcoholic nonsmokers, and 0.64 in nonalcoholic nonsmokers (chi2 = 11.1, 3 df, p = 0.011). Women showed a main effect of Val158 on smoking (p=0.003). Both male and female alcoholics were more likely to have at least 1 Val158 allele compared with nonalcoholics (0.95 vs 0.88, p < 0.05). Approximately 30% of all participants were long-term, nonaddicted light, social smokers (3.6+/-1.7 cigarettes/d); they had the same Val158Met frequencies as nonsmokers. Haplotype analyses supported the Val158Met findings; however, only 1 of the 2 Val158 haplotypes was implicated. CONCLUSIONS: Plains Indians have different smoking and drinking patterns and considerably less comorbidity between alcoholism and heavy smoking compared with the general U.S. population. Our COMT Val158Met results suggest that there may be both sex differences in the genetic origins of alcoholism and smoking in this population and overlap in genetic vulnerability to both addictions in women.

Adult↗
PubMed2006

Using ancestry-informative markers to define populations and detect population stratification.

A serious problem with case-control studies is that population subdivision, recent admixture and sampling variance can lead to spurious associations between a phenotype and a marker locus, or indeed may mask true associations. This is also a concern in therapeutics since drug response may differ by ethnicity. Population stratification can occur if cases and controls have different frequencies of ethnic groups or in admixed populations, different fractions of ancestry, and when phenotypes of interest such as disease, drug response or drug metabolism, also differ between ethnic groups. Although most genetic variation is inter-individual, there is also significant inter-ethnic variation. The International HapMap Project has provided allele frequencies for approximately three million single nucleotide polymorphisms (SNPs) in Africans, Europeans and East Asians. SNP variation is greatest in Africans. Statistical methods for the detection and correction of population stratification, principally Structured Association and Genomic Control, have recently become freely available. These methods use marker loci spread throughout the genome that are unlinked to the candidate locus to estimate the ancestry of individuals within a sample, and to test for and adjust the ethnic matching of cases and controls. To date, few case-control association studies have incorporated testing for population stratification. This paper will focus on the debate about the quantity and methods for selection of highly informative marker loci required to characterize populations that vary in substructure or the degree of admixture, and will discuss how these theoretically desirable approaches can be effectively put into practice.

Case-Control Studies↗
PubMed2005

Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations.

CONTEXT: Tryptophan hydroxylase 2 (TPH2) encodes the rate-limiting enzyme for brain serotonin biosynthesis. It was recently reported that the TPH2 haplotype was linked to depression in humans. OBJECTIVE: To determine the association of TPH2 with suicide attempt, major depression, and a neurochemical intermediate phenotype, cerebrospinal fluid 5-hydroxyindoleacetic acid. DESIGN: We resequenced TPH2 coding, 5' promoter, 3'-untranslated region, and splice junction regions in 190 individuals selected for ethnic and clinical diversity, determined haplotype structure using 15 single nucleotide polymorphisms spanning 106 kilobases (kb), and performed linkage analysis in 1798 cases and controls representing 4 populations (657 African Americans, including 104 suicide attempters and 135 with major depression; 513 Finnish whites, including 150 suicide attempters; 146 US whites, including 81 with depression, anxiety disorder, or both; and 482 southwestern American Indians, including 123 suicide attempters and 191 with depression, anxiety disorder, or both) and in 94 Finnish whites for cerebrospinal fluid 5-hydroxyindoleacetic acid levels. RESULTS: Sixteen single nucleotide polymorphisms, including Pro206Ser, were detected. The 15-locus panel defined and maximized information content from 2 haplotype blocks in whites, 3 haplotype blocks in African Americans, and the single haplotype block spanning TPH2 in southwestern American Indians. Among common Block1b haplotypes were 2 in yin and yang (opposite) configuration, indicating ancient origin. The yin haplotype, 212121, was increased in frequency in suicide attempters in both populations tested (Finnish whites and African Americans). It was associated with major depression and anxiety disorders in US whites and with major depression in African Americans. The yin haplotype was moderately predictive of lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations in controls but not in cases. CONCLUSION: Haplotype linkage of TPH2 to suicide attempt and major depression and to a mediating phenotype, cerebrospinal fluid 5-hydroxyindoleacetic acid, provides preliminary evidence of a functional locus potentially within a haplotype block at least 52 kb in size.

Adult↗
PubMed2005

Haplotype structure of the beta adrenergic receptor genes in US Caucasians and African Americans.

The beta-adrenergic receptors (beta-AR) are G protein-coupled receptors activated by epinephrine and norepinephrine and are involved in a variety of their physiological functions. Previously, three beta-AR genes (ADRB1, ADRB2 and ADRB3) were resequenced, identifying polymorphisms that were used in genetic association studies of cardiovascular and metabolic disorders. These studies have produced intriguing but inconsistent results, potentially because the known functional variants: ADRB1 Arg389Gly and Gly49Ser, ADRB2 Arg16Gly and Gln27Glu, and ADRB3 Arg64Trp provided an incomplete picture of the total functional diversity at these genes. Therefore, we created marker panels for each beta-AR gene that included the known functional markers and also other markers evenly spaced and with sufficient density to identify haplotype block structure and to maximize haplotype diversity. A total of 27 markers were genotyped in 96 US Caucasians and 96 African Americans. In both populations and for each gene, a single block with little evidence of historical recombination was observed. For each gene, haplotype captured most of the information content of each functional locus, even if that locus was not genotyped, and presumably haplotype would capture the signal from unknown functional loci whose alleles are of moderate abundance. This study demonstrates the utility of using beta-AR gene haplotype maps and marker panels as tools for linkage studies on beta-AR function.

Black or African American↗
PubMed2005

BDNF variation and mood disorders: a novel functional promoter polymorphism and Val66Met are associated with anxiety but have opposing effects.

The brain-derived neurotrophic factor (BDNF) gene is critical for neuronal function and survival, and is likely to be important in psychiatric disorders. In this study, we used single-nucleotide polymorphism (SNP) discovery, functional analyses, and genetic association studies to better understand the potential role of BDNF sequence variation in behavior. Screening 480 unrelated individuals for SNPs and genotyping was performed in US Caucasian, American Indian, and African American populations. Lifetime DSM-III-R psychiatric diagnoses were assigned and the Tridimensional Personality Questionnaire (TPQ) was administered to measure anxious temperament (harm avoidance (HA)) and novelty seeking (NS). A novel SNP (-281 C>A) in promoter 1 was discovered that had decreased DNA binding in vitro and decreased basal reporter gene activity in transfected rat hippocampal neurons. The frequency of the -281 A allele was 0.03 in a Caucasian sample, but was virtually absent in other populations. Association analyses in a community-based sample showed that individuals with the -281 A allele (13 heterozygotes) had lower TPQ HA (F=4.8, p<0.05). In contrast, the Met 66 allele was associated with increased HA (F=4.1, p=0.02) and was most abundant in individuals with both anxiety disorders and major depression (p<0.05). Among the Val66Val homozygotes, individuals who were -281 CA heterozygotes had significantly lower HA than the -281 CC homozygotes (p<0.01). Our results suggest that in this population, the low activity -281 A allele may be protective against anxiety and psychiatric morbidity, whereas Met 66 may be a risk allele.

Adult↗
PubMed2005

Thr105Ile, a functional polymorphism of histamine N-methyltransferase, is associated with alcoholism in two independent populations.

BACKGROUND: Histamine is expressed in cortical and limbic areas that are involved in emotion and cognition and modulates these behaviors. H1 receptor antagonists are sedative. Histamine N-methyltransferase (HNMT) catalyzes the Ntau methylation of histamine, the sole pathway for termination of the neurotransmitter action of histamine in mammalian brain. A common and functionally significant polymorphism, a C314T transition in exon 4 of the HNMT gene results in a Thr105Ile substitution of the protein encoded. The Thr105 allele is associated with approximately 2-fold higher enzyme activity, leading to the prediction that it might be associated with diminished histamine levels, resulting in differences in anxiety, cognition, and sedation that play important roles in alcoholism. In two ethnically distinct populations, we tested whether the Thr105Ile polymorphism was associated with alcoholism and with harm avoidance, a dimensional measure of anxious personality. METHODS: A 5' exonuclease assay (TaqMan) was used to genotype Thr105Ile in psychiatrically interviewed Finnish Caucasian (n = 218) and Plains American Indian (n = 186) alcoholics, along with ethnically matched, psychiatrically interviewed, controls (Finns: n = 313, Plains Indian: n = 140). RESULTS: Ile105 allele frequencies were significantly lower in alcoholics compared with nonalcoholics in both populations (Finns: 0.12 vs. 0.17, chi(2) = 6, p = 0.015; Plains Indians: 0.03 vs. 0.08, chi(2) = 5, p = 0.023). Genotype distributions also differed significantly. In Finns, Ile105 showed borderline significance for an association with lower harm avoidance (p = 0.070) after correcting for alcoholism diagnosis. CONCLUSIONS: Decreased levels of brain histamine consequent to the Thr105 allele may result in higher levels of anxiety and, as a consequence, vulnerability to alcoholism.

Adult↗
PubMed2004

Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene.

The alpha 2-adrenergic receptors (alpha2-AR) mediate physiological effects of epinephrine and norepinephrine. Three genes encode alpha2-AR subtypes carrying common functional polymorphisms (ADRA2A Asn251Lys, ADRA2B Ins/Del301-303 and ADRA2C Ins/Del322-325). We genotyped these functional markers plus a panel of single nucleotide polymorphisms evenly spaced over the gene regions to identify gene haplotype block structure. A total of 24 markers were genotyped in 96 Caucasians and 96 African Americans. ADRA2A and ADRA2B each had a single haplotype block at least 11 and 16 kb in size, respectively, in both populations. ADRA2C had one haplotype block of 10 kb in Caucasians only. For the three genes, haplotype diversity and the number of common haplotypes were highest in African Americans, but a similar number of markers (3-6) per block was sufficient to capture maximum diversity in either population. For each of the three genes, the haplotype was capable of capturing the information content of the known functional locus even when that locus was not genotyped. The alpha2-AR haplotype maps and marker panels are useful tools for genetic linkage studies to detect effects of known and unknown alpha2-AR functional loci.

Black or African American↗
PubMed2004

Haplotype architecture of the norepinephrine transporter gene SLC6A2 in four populations.

The norepinephrine transporter (NET) regulates levels of monoamine neurotransmitters integral to a variety of behaviors and autonomic functions. Two SLC6A2 polymorphisms have been used in genetic association studies, generating intriguing but nondefinitive results on traits such as hypertension and mood. One of these SLC6A2 variants is functional but rare. The other is common but not informative over the entire 48 kb SLC6A2 region and is insufficient to capture the functional diversity potentially contained within any SLC6A2 region. To elucidate SLC6A2 haplotype structure and define markers sufficient to capture haplotype diversity within detected haplotype blocks, 26 single-nucleotide polymorphisms (SNPs) were genotyped in 384 individuals evenly divided across Finnish Caucasian, US Caucasian, Plains American Indian, and African American populations. Three conserved blocks, 13.6, 12.5, and 25 kb in size and showing little evidence for historical recombination were observed in all populations. Haplotype diversity in block 1 and numbers of common haplotypes were highest in African Americans, among whom 5-6 optimal markers were sufficient to maximize diversity of each block. For other populations, 2-3 markers/block sufficed, but the optimal markers differed across populations. The SLC6A2 haplotype map and 25-marker panel (excluding the monomorphic one) is a comprehensive tool for genetic linkage studies on phenotypes related to NET function.

Black or African American↗
PubMed2003

Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism.

OBJECTIVE: Women are more prone to anxiety than men. The catechol- -methyltransferase functional polymorphism, Val158Met, is likely to be implicated in anxiety vulnerability. We hypothesized that, particularly in women, the low-activity Met158 allele would be associated with higher anxiety scores and a biological trait, low-voltage alpha resting electroencephalogram (EEG), previously associated with alcoholism and anxiety disorders. METHODS: DNA was obtained from two independent groups of participants ascertained as community samples: 149 predominantly Caucasian individuals (92 women, 57 men), and 252 Plains American Indians (149 women, 103 men). Dimensional measures of anxiety (Tridimensional Personality Questionnaire harm avoidance subscales HA1 and HA2) were obtained and DSM-III-R lifetime psychiatric diagnoses were determined. EEGs were recorded and EEG phenotypes assigned. RESULT: In both populations, women showed significant associations between catechol- -methyltransferase genotype and elevated harm avoidance scores, and the Met158/Met158 genotype was most strongly associated: predominantly Caucasian participants: HA1, P=0.03, HA2, P =0.03; and Plains American Indians: HA2, P=0.01. This was also the case with low-voltage alpha resting EEG: predominantly Caucasian participants: P=0.01, odds ratio=5.0 (95% confidence interval, 1.3-18.7); Plains American Indians: P=0.03, odds ratio=3.7 (95% confidence interval, 1.1-12.7). CONCLUSIONS: The results of the present study suggest that an inherited difference in catecholamine metabolism is important in the pathogenesis of anxiety in women.

Anxiety Disorders↗
PubMed2003

Genetics of alcoholism using intermediate phenotypes.

This article represents the proceedings of a symposium at the 2002 meeting of the Research Society on Alcoholism in San Francisco, CA. It was organized by Mary-Anne Enoch and David Goldman and chaired by David Goldman. The presentations were (1) Two functional polymorphisms and their intermediate phenotypes in complex behaviors: COMT/executive cognition and anxiety and HTT/anxiety, by David Goldman; (2) Role of the EEG in determining genetic risk for alcoholism and anxiety disorders, by Mary-Anne Enoch; (3) The response to alcohol as an intermediate phenotype for alcoholism, by Marc A. Schuckit; and (4) Pharmacogenomic approaches to alcoholism treatment: toward a hypothesis, by Bankole A. Johnson.

Alcohol Drinking↗
PubMed2003

Pharmacogenomics of alcohol response and addiction.

Alcoholism is a complex psychiatric disorder that has high heritability (50-60%) and is relatively common; in the US the lifetime prevalence of alcohol dependence is 20% in men and 8% in women. Current psychosocial and pharmacological therapies have relatively modest effects. Treatment is complicated by the fact that alcoholism is often co-morbid with other disorders, including anxiety, depression, and antisocial personality disorder. Approximately 80% of alcoholics smoke cigarettes and there is considerable genetic overlap between nicotine and alcohol addiction. Convergent evidence supports the classification of alcoholics into two broad categories: type 1 - later onset with feelings of anxiety, guilt, and high harm avoidance; and type 2 - early age of onset, usually men, impulsive, antisocial, and with low levels of brain serotonin. The pharmacogenomics of alcohol response is well established; genetic variants for the principal enzymes of alcohol metabolism influence drinking behavior and protect against alcoholism. Vulnerability to alcoholism is likely to be due to multiple interacting genetic loci of small to modest effects. First-line therapeutic targets for alcoholism are neurotransmitter pathway genes implicated in alcohol use. Of particular interest are the 'reward pathway' (serotonin, dopamine, GABA, glutamate, and beta endorphin) and the behavioral stress response system (corticotrophin-releasing factor and neuropeptide Y). Common functional polymorphisms in these genes are likely to be predictive (although each with small effect) of individualized pharmacological responses. Genetic studies, including case-control association studies and genome wide linkage studies, have identified associations between alcoholism and common functional polymorphisms in several candidate genes. Meanwhile, the current pharmacological therapies for alcoholism are effective in some alcoholics but not all. Some progress has been made in elucidating the pharmacogenomic responses to these drugs, particularly in the context of the type 1/type 2 classification system for alcoholics.

Alcohol Drinking↗
PubMed2002

Problem drinking and alcoholism: diagnosis and treatment.

Alcoholism is one of the most common psychiatric disorders with a prevalence of 8 to 14 percent. This heritable disease is frequently accompanied by other substance abuse disorders (particularly nicotine), anxiety and mood disorders, and antisocial personality disorder. Although associated with considerable morbidity and mortality, alcoholism often goes unrecognized in a clinical or primary health care setting. Several brief screening instruments are available to quickly identify problem drinking, often a pre-alcoholism condition. Problem drinking can be successfully treated with brief intervention by primary care physicians. Alcohol addiction is a lifelong disease with a relapsing, remitting course. Because of the potentially serious implications of the diagnosis, assessment for alcoholism should be detailed. Alcoholism is treated by a variety of psychosocial methods with or without newly developed pharmacotherapies that improve relapse rates. Screening for problem drinking and alcoholism needs to become an integral part of the routine health screening questionnaire for adolescents and all adults, particularly women of child-bearing age, because of the risk of fetal alcohol syndrome.

Alcohol Drinking↗
PubMed2002

The relationship between two intermediate phenotypes for alcoholism: low voltage alpha EEG and low P300 ERP amplitude.

OBJECTIVE: There is considerable evidence that the amplitude of the heritable P300 event-related potential (ERP) is reduced in alcoholics and their alcohol-naive children. Low voltage alpha (LVA), a heritable resting electroencephalogram (EEG) trait present in 7-14% of the population, has been shown to be associated with alcoholism and anxiety disorders. A few studies have demonstrated a modest correlation between pre-stimulus alpha power and P300 amplitude. We aimed to test this finding in community volunteers, hypothesizing that LVA would be associated with low P300 amplitude. METHOD: Digitized resting EEG was recorded at the central parietal site (Pz) from 85 male and 113 female community volunteers (120 unrelated). ERPs were elicited at Pz by auditory and visual oddball paradigms. All participants were interviewed with the Schedule for Affective Disorders, Lifetime Version (SADS-L) and assigned blind-rated psychiatric diagnoses according to the American Psychiatric Association DSM-III-R criteria. RESULTS: LVA participants (including alcoholics and nonalcoholics) had significantly lower auditory and visual P300 amplitudes. Absolute alpha power was modestly correlated with auditory and visual P300 amplitude and was associated with 9.4% and 4.6% of the variance, respectively. CONCLUSIONS: The association between LVA and low P300 amplitude, two distinct electrophysiological traits, suggests that, at least in individuals with the LVA trait, some aspects of resting, unstimulated brain activity and activated brain function in the form of attentional response may be fundamentally related.

Adolescent↗