Genome-wide association study of theta band event-related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence.

Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome-wide association study (GWAS) of an ERO endophenotype-frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty-two SNPs of the Illumina HumanHap 1 M microarray were selected from the theta ERO GWAS for replication in family-based samples (N = 1,095), with four markers revealing nominally significant association.

Referral patterns of Indiana oncologists for colorectal cancer genetic services.

We assessed the utilization and referral patterns of Indiana oncologists for colorectal cancer (CRC) genetic services. Surveys were sent to 151 oncologists practicing within the state, with a response rate of 40%. Half of respondents had previously referred patients for CRC genetic services.

GABRR1 and GABRR2, encoding the GABA-A receptor subunits rho1 and rho2, are associated with alcohol dependence.

The genes encoding several GABA-A receptor subunits, including GABRA2, have been associated with alcoholism, suggesting that variations in gaba signaling contribute to risk. Therefore, as part of a comprehensive evaluation of the GABA receptor genes, we evaluated the potential association of GABRR1 and GABRR2, which encode the rho1 and rho2 subunits of the pentameric GABA-A/GABA-C receptors. GABRR1 and GABRR2 lie in a head to tail orientation spanning 137 kb on chromosome 6q14-16.

Association of the calcium-sensing receptor gene with blood pressure and urinary calcium in African-Americans.

Context: Calcium binding to the Ca-sensing receptor (CASR) expressed in thick ascending limb inhibits the Na,K,2Cl cotransporter, which decreases sodium reabsorption and secondarily decreases Ca reabsorption. CASR gene variants could influence blood pressure (BP) by affecting Na retention.

Objective: The objective of the study was to determine whether variations in CASR associated with BP in African-Americans, an ethnic group at high risk for hypertension.

The tachykinin receptor 3 is associated with alcohol and cocaine dependence.

Background: A broad region on chromosome 4q was previously linked to the phenotype of alcohol dependence in the Collaborative Study on the Genetics of Alcoholism sample. A strong positional candidate gene was identified within this region: tachykinin receptor 3 gene (TACR3), which encodes tachykinin receptor 3 (NK3R), the receptor for the tachykinin 3 (neurokinin B) peptide. Pharmacological studies have provided evidence that the administration of NK3R agonists attenuates the intake of alcohol and NK3R can also mediate the acute and chronic behavioral effects of cocaine.

Association of NFKB1, which encodes a subunit of the transcription factor NF-kappaB, with alcohol dependence.

A broad region on chromosome 4q has been linked to alcohol dependence (alcoholism). We hypothesized that such broad linkage regions represent the combined action of multiple genes. Seeking to identify genes within that region that are associated with alcoholism, we have tested the association of NFKB1, located at 4q24, with alcoholism.

Association analysis of genes encoding the nociceptin receptor (OPRL1) and its endogenous ligand (PNOC) with alcohol or illicit drug dependence.

Recent studies in animal models have shown that the nociceptin system, comprising nociceptin (or OFQ/N, encoded by PNOC) and the nociceptin receptor (an opioid receptor-like protein encoded by OPRL1), may be involved in alcohol and other drug reward pathways. To determine whether the nociceptin system is associated with alcohol or illicit drug dependence in humans, we analyzed 10 single nucleotide polymorphisms (SNPs) in OPRL1 and 15 SNPs in PNOC in a sample of 1923 European Americans from 219 multiplex alcohol dependent families ascertained by the Collaborative Study on the Genetics of Alcoholism. The SNPs spanned both genes and several kb of their flanking sequences, and were in high linkage disequilibrium.

Unique facial features distinguish fetal alcohol syndrome patients and controls in diverse ethnic populations.

Background: Effective management of fetal alcohol spectrum disorders (FASD) is dependent on the timely and reliable diagnosis of affected individuals. There are significant diagnostic difficulties because of the reduced prominence of facial features as children age to adulthood as well as potential population or ethnic differences in the most characteristic alcohol-related facial features.

Methods: A total of 276 subjects were recruited from 4 sites (Cape Town, South Africa; Helsinki, Finland; Buffalo, New York; and San Diego, California) and completed a detailed dysmorphology evaluation to classify subjects as either fetal alcohol syndrome (FAS; 43%) or control (57%).

Association of the aldehyde dehydrogenase 2 promoter polymorphism with alcohol consumption and reactions in an American Jewish population.

Background: Reduction in activity of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) enzyme due to genetic deficiency causes reactions related to alcohol consumption and lowers the risk of alcoholism. ALDH2*2 is the only functionally significant polymorphism of the ALDH2 gene. An additional polymorphic locus in the promoter (G to A substitution approximately 360 bp from the translation start site) may influence ALDH2 activity through effects on transcriptional activity.

Lack of association of alcohol dependence and habitual smoking with catechol-O-methyltransferase.

Objective: To test whether variation in the gene encoding the enzyme catechol-O-methyltransferase (COMT), which catalyzes the breakdown of dopamine and other catecholamine neurotransmitters, is associated with the risk for alcohol dependence and habitual smoking.

Methods: Single nucleotide polymophisms (SNPs) were genotyped in a sample of 219 multiplex alcohol-dependent families of European American descent from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based tests of association were performed to evaluate the evidence of association between the 18 SNPs distributed throughout COMT, including the functional Val158Met polymorphism, and the phenotypes of alcohol dependence, early onset alcohol dependence, habitual smoking, and comorbid alcohol dependence and habitual smoking.

The opioid system in alcohol and drug dependence: family-based association study.

Opioid receptors and their endogenous peptide ligands play important roles in neurotransmission and neuromodulation in response to addictive drugs such as heroin, cocaine, and alcohol. In an earlier study, we reported that variation in the genes encoding the kappa-opioid receptor (OPRK1) and its peptide ligand (PDYN) were associated with the risk for alcoholism. We continued our investigation of the role of the opioid system in alcohol dependence by analyzing the genes encoding the micro- and delta-opioid receptors and their peptide ligands.

Association of alcohol craving with alpha-synuclein (SNCA).

Background: Studies have found that genomic variation in the gene SNCA, which encodes the protein alpha-synuclein, may contribute to the variation in alcohol consumption in an inbred rat model of alcohol preference. Studies in humans have provided support for an association between SNCA and craving for alcohol.

Methods: To examine the role of this gene in alcohol dependence and related phenotypes, 30 single nucleotide polymorphisms (SNPs) were genotyped across the SNCA gene in a sample of 219 multiplex alcoholic families of European American descent.

Specific psychiatric manifestations among preclinical Huntington disease mutation carriers.

Background: Despite the need for significant clinical intervention owing to the psychiatric manifestations of Huntington disease (HD), there has been a paucity of studies specifically designed to evaluate these symptoms prior to disease diagnosis.

Objectives: To investigate whether the Symptom Checklist 90-Revised (SCL-90-R) and the Center for Epidemiological Studies Depression Scale can be used to detect psychiatric manifestations among preclinical mutation carriers with absent or minimal motor signs of HD.

Design, Setting, And Participants: Individuals at risk for or recently diagnosed with HD were recruited and then evaluated at Indiana University School of Medicine, Indianapolis.

Association between GABRA1 and drinking behaviors in the collaborative study on the genetics of alcoholism sample.

Background: A wealth of literature supports the role of gamma-aminobutyric acid (GABA) in neurobiological pathways contributing to alcohol dependence and related phenotypes. Animal studies have consistently tied rodent homologs of the GABAA receptor genes on human chromosome 5q to alcohol-related behaviors; however, human studies have produced mixed results. Family-based association analyses previously conducted in the Collaborative Study on the Genetics of Alcoholism (COGA) sample yielded no evidence of association with Diagnostic and Statistical Manual of Mental Disorder-fourth edition (DSM-IV) alcohol dependence and these genes.

Association of alcohol dehydrogenase genes with alcohol dependence: a comprehensive analysis.

Linkage evidence indicated that gene(s) located on chromosome 4q, in the region of the alcohol dehydrogenase (ADH) genes, affected risk for alcoholism. We genotyped 110 single nucleotide polymorphisms (SNPs) across the seven ADH genes and analyzed their association with alcoholism in a set of families with multiple alcoholic members, using the pedigree disequilibrium test. There was strong evidence that variations in ADH4 are associated with alcoholism: 12 SNPs were significantly associated.