Biomedical subjects

Marissa A Ehringer

Publications and source records attributed to Marissa A Ehringer.

11 recordsLinked to original sources

PubMed2007

Association of the neuronal nicotinic receptor beta2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine.

Nicotine addiction and alcohol dependence are highly comorbid disorders that are likely to share overlapping genetic components. We have examined two neuronal nicotinic receptor subunit genes (CHRNA4 and CHRNB2) for possible associations with nicotine and alcohol phenotypes, including measures of frequency of use and measures of initial subjective response in the period shortly after first using the drugs. The subjects were 1,068 ethnically diverse young adults participating in ongoing longitudinal studies of adolescent drug behaviors at the University of Colorado, representing both clinical and community samples. Analysis of six SNPs in the CHRNA4 gene provided modest support for an association with past 6 month use of alcohol in Caucasians (three SNPs with P < 0.08), but no evidence for an association with tobacco and CHRNA4 was detected. However, a SNP (rs2072658) located immediately upstream of CHRNB2 was associated with the initial subjective response to both alcohol and tobacco. This study provides the first evidence for association between the CHRNB2 gene and nicotine- and alcohol-related phenotypes, and suggests that polymorphisms in CHRNB2 may be important in mediating early responses to nicotine and alcohol.

Adolescent↗

PubMed2006

Cannabis receptor haplotype associated with fewer cannabis dependence symptoms in adolescents.

Cannabis is a major substance of abuse, and the gene encoding for the central cannabinoid receptor (CNR1) is a logical candidate gene for vulnerability toward developing symptoms of cannabis dependence. We studied four single-nucleotide polymorphisms (SNPs) in the CNR1 gene for association with having one or more symptoms of cannabis dependence in 541 adolescent subjects who had all tried cannabis five or more times. Cases (327) were defined as those who had tried marijuana and developed one or more symptoms, and controls (214) as those who had tried marijuana but developed no dependence symptoms. Cannabis dependence symptoms were assessed in these youth when they were 17 or older with the Composite International Diagnostic Interview--Substance Abuse Module. Univariate (single-marker) association tests demonstrated that SNP rs806380, located in intron 2 of the CNR1 gene, was significantly associated with developing one or more cannabis dependence symptoms, with the G allele having a protective effect (P < 0.02). This was consistent with the results of the global haplotype test (P < 0.01). One of the common haplotypes examined (present in 21% of the subjects) was significantly associated with a lower rate of having one or more cannabis dependence symptoms. Our findings provide evidence suggesting that a common CNR1 haplotype is associated with developing fewer cannabis dependence symptoms among adolescents who have experimented with cannabis.

Adolescent↗

PubMed2006

Relationship between adolescent marijuana use and young adult illicit drug use.

: We examined three components of the "gateway theory" in relation to marijuana use: (1) whether adolescent marijuana use predicts young adult drug use, (2) whether this association persists when controlling for similar family background, (3) whether common genetic or environmental factors contribute to the association. The three components were tested in adolescents from the National Longitudinal Study of Adolescent Health assessed twice during adolescence and then re-interviewed 5 years later. Component 1 was tested in 18,286 subjects, component 2 in sibling pairs (n=360) discordant for marijuana use, and component 3 in a genetically informative sub-sample (n=4846). Marijuana use was defined as any use during adolescence, and drug use was defined as self-reported past year use of other illicit drugs besides marijuana. Marijuana users were twice as likely to use illicit drugs as young adults than non-users. Shared environmental factors mediated much of the relationship between adolescent marijuana use and young adult drug use. The association remained, however, even when controlling for familial environmental and other measured factors.

Adolescent↗

PubMed2006

Genetic and environmental contributions to common psychopathologies of childhood and adolescence: a study of twins and their siblings.

We report findings based on analyses of self-reports of six common adolescent psychopathologies (attention deficit/hyperactivity disorder, ADHD; conduct disorder, CD; oppositional defiant disorder, ODD; generalized anxiety disorder, GAD; separation anxiety disorder, SAD; and major depressive disorder, MDD) in a sample of 1,162 male and female adolescent (12-19 years) twin pairs and 426 siblings. Prevalence statistics for past year and lifetime reports confirm differences between genders for CD, GAD, SAD, and MDD, and a lack of differences between twins and their non-twin siblings. Biometrical modeling was conducted to ascertain the relative influences of genes, and shared and non-shared environments contributing to these disorders. A more robust estimate of these parameters was obtained by including non-twin siblings. Age-specific thresholds were integrated into the analyses to appropriately model the developmental patterns of behavior. We found evidence for both genetic and non-shared environmental influences for all disorders. Shared environmental influences also seem to be important for MDD and lifetime GAD.

Adolescent↗

PubMed2005

Monoamine oxidase A (MAOA) and antisocial behaviors in the presence of childhood and adolescent maltreatment.

There is a robust relationship between the experience of maltreatment in childhood and later antisocial behaviors amongst adolescents and adults. Animal and human studies suggest that variation in monoamine oxidase A (MAOA) genotype may moderate the effects of maltreatment. Self-reported conduct problems and criminal convictions amongst sibling-pairs from the National Longitudinal Study of Adolescent Health were tested for association with reports of maltreatment before and after the age of 12. MAOA promoter polymorphisms were tested for possible moderation effects. Maltreatment predicted conduct problems and criminal convictions. MAOA genotype did not have a significant moderating effect in any of the six analyses that were conducted. We did not replicate a previous report that MAOA polymorphisms moderated the relationship between maltreatment and conduct problems. There was, however, a non-significant trend in the predicted direction. Additional studies will be needed before firm conclusions can be drawn about this hypothesized genotype-environment interaction.

Adolescent↗

PubMed2004

Genetic influences on quantity of alcohol consumed by adolescents and young adults.

OBJECTIVE: To examine genetic and environmental influences on drinking in a nationally representative study of genetically informative adolescents followed into young adulthood. METHOD: The average quantity of alcohol used per drinking episode during the past year was analyzed in 4432 youth assessed during adolescence (mean age of 16) and then 1 and 6 years later. The variance of quantity of alcohol consumed was decomposed into three components: additive genetic (a2), shared environmental (c2), non-shared environmental (e2). Four candidate genes were tested for association. RESULTS: Wave 1 a2-0.52e2-0.48, Wave 2 a2-0.28e2-0.72, Wave 3 a2-0.30e2-0.70. Genetic correlations between Waves 1 and 2 were 0.85, Waves 1 and 3 were 0.34. The DAT1 440 allele was associated at Wave 1 (p=0.007). DRD2 TaqI A1/A2 was associated at Wave 3 (p=0.007). DRD4 and 5HTT were not associated. The DAT1 and DRD2 polymorphisms accounted for 3.1% and 2.0% of the variation, respectively. CONCLUSION: Genetic influence on drinking behavior was common in adolescents longitudinally assessed 1 year apart, but was less correlated between these adolescents and their assessment as young adults at a subsequent time point. Polymorphisms in genes of the dopaminergic system appear to influence variation in drinking behavior.

Adolescent↗

PubMed2003

Variants of kappa-opioid receptor gene and mRNA in alcohol-preferring and alcohol-avoiding mice.

Results of recent studies have indicated an association between voluntary alcohol intake and activities of kappa-opioid receptor systems in animal models. We assessed the possibility that genetic differences observed in alcohol preference among mouse strains are related to possible polymorphisms of the kappa-opioid receptor gene (Oprk1). We compared DNA sequences of the coding region and the promoter/regulatory region of Oprk1 among C57BL/6ByJ (B6, alcohol-preferring), BALB/cJ (alcohol-avoiding), CXBI (alcohol-avoiding), and six B6.C and B6.I Recombinant QTL Introgression (RQI) strains, which carry approximately 3% of the donor BALB/cJ genome in the background B6 genome and showed various alcohol preferences. Although there were no sequence differences in the coding region, BALB/cJ had a single nucleotide polymorphism (SNP) in the promoter region, which was not detected in other strains. The results indicate that the difference in alcohol preference between B6 and BALB/cJ is not correlated with polymorphisms of Oprk1. However, results of further studies comparing Oprk1 mRNA expression between B6 and BALB/cJ showed that Oprk1 expression is regulated differently in these strains. Also, DBA/2J mice (alcohol-avoiding) showed expression of Oprk1 mRNA subtypes (alternatively spliced) different from B6 and BALB/cJ mice. Search of the Celera Genomics database indicated that DBA/2J had several SNP sites in the promoter/regulatory regions, which might explain the different expression of Oprk1 mRNA subtypes in this strain. The strain-dependent variation in the expression of alternatively spliced genes can be a significant source of phenotypic variation of complex traits such as alcohol preference.

Alcohol Drinking↗

PubMed2002

Human alcoholism studies of genes identified through mouse quantitative trait locus analysis.

Coding region DNA sequence variants have been recently identified in several QTL candidate genes in a mouse model of differential sensitivity to alcohol [inbred long-sleep (ILS) and inbred short-sleep (ISS)]. This work has been extended into a human population characterized for their initial level of response to alcohol (LR). The coding region of one of the most promising of these candidate genes, zinc finger 133 (Znf133), has been sequenced completely in 50 individuals who participated in alcohol challenges at approximately age 20 and have been followed subsequently for the last 15 years. PCR products were obtained for the protein coding region of ZNF133 using human genomic DNA and directly sequenced using automated sequencers. Novel single nucleotide polymorphisms (SNPs) were detected by analyzing the sequence data using a suite of bioinformatics programs including Consed, Phred, Phrap and Polyphred. Five human SNPs were detected, two that correspond to amino acid changes in the protein, two that are silent DNA changes and one located in an intron. In this small sample, no significant association between any of the SNPs and alcohol diagnosis was detected. A follow-up of these SNPs in a larger sample should allow a more definitive conclusion to be reached. Significantly, the data presented here demonstrate the feasibility of directly testing genes in human alcoholic populations that had been identified first by comparative DNA sequencing of candidate genes located within mouse alcohol-related QTLs, even without detailed knowledge of the gene's function.

Adult↗

PubMed2002

Fine mapping of polymorphic alcohol-related quantitative trait loci candidate genes using interval-specific congenic recombinant mice.

BACKGROUND: The inbred long-sleep (ILS) and inbred short-sleep (ISS) strains of mice are widely studied as a model of initial sensitivity to alcohol. Recently, a large comparative DNA sequencing study of candidate genes located within the four Lore quantitative trait loci (QTLs) associated with the ethanol-induced loss of righting reflex in ILS and ISS mice has identified eight genes that contain coding region differences corresponding to amino acid changes. Here, recently developed interval-specific congenic recombinant mice (ISCRs) have been used to map these genes in relationship to newly narrowed QTL regions. METHODS: Regions of candidate genes containing DNA differences corresponding to previously identified amino acid changes between ISS and ILS mice were amplified from either genomic DNA or complementary DNA from ISCR mice using polymerase chain reaction. The products were purified and directly sequenced to determine the genotypes for each polymorphism. On the basis of these genotypic data, each candidate gene was determined to be located either within or outside of recently narrowed Lore QTL intervals. RESULTS: Of these eight candidates with protein-coding differences, five are now excluded from their respective Lore intervals. The other three (Znf142, Ptprn, and Znf133) have been localized to the narrowed QTL intervals. CONCLUSIONS: These three central nervous system genes (Znf142, Ptprn, and Znf133) represent promising candidates for involvement in the differential sensitivity to alcohol exhibited between ILS and ISS mice. This study also demonstrates how the combination of high-throughput comparative gene sequencing and concomitant genetic fine mapping of QTL regions with ISCRs can be an effective tool for accelerating the process of moving from QTL to gene.

Alcoholism↗

PubMed2002

Quantitative trait loci affecting initial sensitivity and acute functional tolerance to ethanol-induced ataxia and brain cAMP signaling in BXD recombinant inbred mice.

In previous work, we identified genetic correlations between cAMP accumulation in the cerebellum and sensitivity to the incoordinating effects of ethanol. A genetic correlation suggests that common genes underlie the phenotypes investigated. One method for provisionally identifying genes involved in a given phenotypic measure is quantitative trait locus (QTL) analysis. Using a panel of 30 BXD recombinant inbred strains of mice and the progenitors (DBA/2J and C57BL/6J), and the dowel test for ataxia, we measured the blood ethanol concentrations at the time an animal first fell from the dowel and acute functional tolerance (AFT), and investigated cAMP signaling in the cerebellum. Cyclic AMP accumulation was measured in whole-cell preparations of cerebellar minces from individual mice under basal or stimulated conditions. We conducted a genome-wide QTL analysis of the behavioral and biochemical measures with >2000 genetic markers to identify significant associations. Western blot and comparative sequencing analysis were used to compare cAMP response element binding protein (CREB) levels and protein-coding sequence, respectively. QTL analyses correlating strain means with allelic status at genetic markers identified several significant associations (p < 0.01). Analysis of variance revealed an effect of strain on behavioral and biochemical measures. There was a significant genetic correlation between initial sensitivity and basal cAMP accumulation in the cerebellum. We identified 6 provisional QTLs for initial sensitivity on four chromosomes, 6 provisional QTLs for AFT on four chromosomes, and 11 provisional QTLs for cAMP signaling on nine chromosomes. Two loci were found to overlap for measures of initial sensitivity and for cAMP signaling. Given the genetic correlation between initial sensitivity and basal cAMP accumulation, we investigated candidate genes in a QTL on chromosome 1. Comparative sequence analysis was performed, and protein levels were compared between C57 and DBA mice for Creb1. No significant differences were detected in coding sequence or protein levels for CREB. These results suggest that although ethanol sensitivity and cAMP signaling are determined by multiple genes, they may share certain genetic codetermination.

Adrenergic beta-Agonists↗

PubMed2002

Genomic approaches to the genetics of alcoholism.

When studying complex diseases such as alcoholism that develop as a result of numerous genetic and environmental factors, researchers can use the sequence data that have become available both for the human and for animal genomes. For these analyses, investigators are being aided by efforts to identify and characterize functionally relevant DNA sequences in the entire genomic DNA sequence--a process called annotation. Various bioinformatics and annotation tools can help in this enterprise. These include four primary approaches: (1) precomputed, annotated public Web sites that provide a plethora of information; (2) in-house analyses from which users can choose the appropriate analyses for their purposes; (3) Web-based annotation systems that analyze a user's DNA sequence; and (4) private resources that provide access to annotated genomic sequences at cost. In addition to careful study of the DNA sequence for clues about function, expression studies of mRNA levels using gene chips provide information about the activity levels of thousands of genes that may vary in different tissues, different animals and people, or under different environmental conditions.

Alcoholism↗