The role of oxytocin and oxytocin receptor gene variants in childhood-onset aggression

Aggressive antisocial behaviours are the most common reasons why adolescents are referred to mental health clinics. Antisocial behaviours are costly in social and financial terms. The aetiology of aggressive behaviours is unknown but growing evidence suggests it is heritable, and certain genetic variants have been implicated as contributing factors. The purpose of this study was to determine whether genes regulating the hormone oxytocin (OXT) were associated with aggressive antisocial behaviour. The case-control study sample consisted of 160 cases of children displaying extreme, persistent and pervasive aggressive behaviour. This case sample was compared with 160 adult controls. We used polymerase chain reaction (PCR) to determine the genotype for three oxytocin gene (OXT) single nucleotide polymorphisms (SNPs): rs3761248, rs4813625 and rs877172; and five oxytocin receptor gene (OXTR) SNPs: rs6770632, rs11476, rs1042778, rs237902 and rs53576. Genotypic analyses were performed using stata, while differences in haplotypic and allelic frequencies were analysed using Unphased. We also performed within-case analyses (n = 236 aggressive cases) examining genotypic and allelic associations with callous-unemotional (CU) scores (as measured by the psychopathic screening device). OXTR SNPs rs6770632 and rs1042778 may be associated with extreme, persistent and pervasive aggressive behaviours in females and males, respectively. These and haplotype results suggest gender-specific effects of SNPs. No significant differences were detected with respect to CU behaviours. These results may help to elucidate the biochemical pathways associated with aggressive behaviours, which may aid in the development of novel medications.     

Association between Oxytocin Receptor Gene Polymorphisms and Self-Rated ‘Empathic Concern’ in Schizophrenia

The nonapeptide oxytocin (OXT) and its receptor (OXTR) have been implicated in social cognition, empathy, emotion and stress regulation in humans. Previous studies reported associations between OXT and OXTR genetic polymorphisms and risk for disorders characterized by impaired socio-emotional functioning, such as schizophrenia and autism. Here we investigate the influence of two single nucleotide polymorphisms (SNPs) within the OXTR gene on a measure of socio-emotional functioning in schizophrenic patients. OXTR SNPs that were previously investigated in other studies were genotyped in 145 patients diagnosed with schizophrenia according to DSM-IV and 145 healthy controls matched for age and gender. The Interpersonal Reactivity Index (IRI) was used to assess cognitive (‘perspective taking’), affective (‘empathic concern’) and self-related (‘personal distress’) dimensions of empathy. No group differences in genotype frequencies were observed. MANCOVA revealed a significant main (F [1,282] = 10.464; p<0.01) and interaction effect (genotype by diagnosis: F [1,282] = 4.329; p<0.05) of OXTR SNP rs2254298(A>GG) with ‘empathic concern’. Within the schizophrenia group, linear regression analysis determined OXTR rs2254298 genotype, PANSS negative and general symptom score, and age of disease onset as being significantly associated with ‘empathic concern’. OXTR rs2254298 significantly impacted PANSS general psychopathology scores. No associations were found for OXTR rs53576, IRI ‘perspective taking’ or ‘personal distress’ ratings. Our preliminary findings support hypotheses about an involvement of OXTR rs2254298 in emotional empathy in schizophrenic and healthy individuals, warranting independent replication.     

No Association between Oxytocin Receptor (OXTR) Gene Polymorphisms and Experimentally Elicited Social Preferences

Background

Oxytocin (OXT) has been implicated in a suite of complex social behaviors including observed choices in economic laboratory experiments. However, actual studies of associations between oxytocin receptor (OXTR) gene variants and experimentally elicited social preferences are rare.

Methodology/Principal Findings

We test hypotheses of associations between social preferences, as measured by behavior in two economic games, and 9 single nucleotide polymorphisms (SNPs) of the OXTR gene in a sample of Swedish twins (n = 684). Two standard economic games, the dictator game and the trust game, both involving real monetary consequences, were used to elicit such preferences. After correction for multiple hypothesis testing, we found no significant associations between any of the 9 single nucleotide polymorphisms (SNPs) and behavior in either of the games.

Conclusion

We were unable to replicate the most significant association reported in previous research between the amount donated in a dictator game and an OXTR genetic variant.     

Male infertility is not liked with HSF1, HSF2 and UBE2I gene polymorphisms among Indian subjects

We analysed the polymorphisms at rs78202224 (C/A) for HSF1 gene, rs139496713 (C/T) and rs45504694 (C/A) for HSF2 gene and rs116868327 (G/A) for UBE2I gene in 547 infertile cases (non-obstructive azoospermia = 464, asthenozoospermia = 83) and 419 proven fertile controls of similar age group and ethnicity. SNP genotyping was done using AgenaMassARRY platform (Agena Bioscience, CA). Common, heterozygous, rare genotypes and allelic frequencies were analysed using dominant, recessive and co-dominant models. Data shows no significant association between HSF1, HSF2 polymorphisms and male infertility. However, under dominant (GG vs GA+AA) and co-dominanat (GG vs GA) model, polymorphism at the rs116868327 (G/A) locus in UBE2I gene was found to be linked with asthenozoospermia in males with a significant odd-ratio of 6.91 (confidence interval at 95% was 1.52-31.46; p=0.017). Moreover, frequency of rare allele was higher (2.4%) compared to controls (0.4%). Thus, this data showed a significant risk of developing asthenozoospermic condition in males (Odds ratio= 6.75; Confidence interval at 95%= 1.50-30.49; P= 0.018]. Hence, more number of genotyping studies along with the functional assay in multiple cohorts is needed to validate potential variants associated with male infertility.     

Association of CHRM2 polymorphisms with severity of alcohol dependence

The cholinergic muscarinic 2 receptor (CHRM2) gene has been considered a candidate gene for the alcohol dependence in that it might underpin certain risk factors for this condition. This study examined variations in the CHRM2 between the patients with alcohol dependence and population controls in Korean and explored the associations between CHRM2 polymorphisms and severity of symptoms in the patients with alcohol dependence. One hundred and fifty-five patients with alcohol dependence, defined by the Alcohol Use Disorders Identification Test (AUDIT) and the Alcohol Dependence Scale (ADS) to measure the severity of symptoms, and one hundred and ninety-five population controls were drawn in the study. Three single nucleotide polymorphisms (SNPs) of CHRM2 were genotyped using the TaqMan assay and analyzed with the severity of symptoms of alcohol dependence. We found that although SNP rs324650 showed marginal association with the risk of alcohol dependence (P = 0.03), the significance of the result was not sustained after multiple corrections. SNP rs1824024 was significantly associated with the AUDIT and ADS scores in patients (P = 0.005 and 0.003, respectively). These findings suggested that the muscarinic acetylcholine function might be related not with alcohol dependence itself but with the severity of alcohol dependence in Korean population.     

Association between promoter variants of interleukin-18 and schizophrenia in a Han Chinese population

An increasing amount of evidence suggests that interleukin-18 (IL-18) plays a pivotal role in the pathophysiology of schizophrenia. However, association between single nucleotide polymorphism of IL-18 and the risk of schizophrenia has not been clarified. This study examined whether two promoter polymorphisms -137 G/C (rs187238) and -607 C/A (rs1946518) of IL-18 were associated with schizophrenia and six clinical symptoms (disorder of perception, thought disorder, disturbance of emotion, disorder of behavior and volition, suicide action, and aggressive action) to provide data for screening high-risk Han Chinese individuals. Three hundred seventy-two schizophrenic patients and 353 healthy controls from a Han Chinese population were examined to assess their genotype and allele frequencies of the two promoter polymorphisms of IL-18. The genotype distributions in both patients and controls were within Hardy-Weinberg equilibrium. No significant differences were observed in the genotype or the allele frequencies of the two single-nucleotide polymorphisms between patients and controls. However, genotype frequencies of -607 C/A showed significant differences between patients and controls in the appearance of perception disorder (χ2 = 6.153, p = 0.046). A significant difference was detected in -137 G/C between patients and controls in the appearance of aggressive action (χ2 = 3.909, p = 0.048). In conclusion, IL-18 gene promoter polymorphisms may not contribute to the susceptibility of schizophrenia in a Han Chinese population, but two single-nucleotide polymorphisms, -137 G/C and -607 C/A, may play a role in the development of perception disorder and aggressive action, respectively.     

Effect of Common Genetic Variants of Growth Arrest-Specific 6 Gene on Insulin Resistance,Obesity and Type 2 Diabetes in an Asian Population

Objectives

Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been implicated in systemic inflammation, obesity, and insulin resistance (IR). Data from recent studies suggest that polymorphisms in the Gas6 gene are associated with cardiovascular disorders and type 2 diabetes (T2D). However, the association of Gas6 gene variants with obesity, IR, and T2D development has not been explored.

Materials and Methods

Four common single nucleotide polymorphisms (SNPs) in the Gas6 gene were genotyped in 984 participants from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. An insulin suppression test was performed to determine IR based on steady-state plasma glucose (SSPG). Associations between IR indices and obesity, and SNP genotypes, based on previously-reported data for this cohort (Phase I), were analyzed. In the present follow-up study (Phase II), the effects of gene variants of Gas6 on the progression to T2D were explored in individuals who were free of T2D in Phase I. The mean follow-up period for Phase II was 5.7 years.

Results

The mean age of the study population in Phase I was 49.5 years and 16.7% of individuals developed T2D during follow-up. After adjusting for covariates, three SNPs (rs8191973, rs8197974, and rs7323932) were found to be associated with SSPG levels (p = 0.007, p = 0.03, and p = 0.011, respectively). This association remained significant after multiple testing and showed a significant interaction with physical activity for SNP rs8191973. However, no other significant correlations were observed between Gas6 polymorphisms and other indices of IR or obesity. A specific haplotype, AACG (from rs8191974, rs7323932, rs7331124, and rs8191973), was positively associated with SSPG levels (p = 0.0098). None of the polymorphisms were associated with an increased risk of T2D development.

Conclusions

Our results suggest that Gas6 gene variants are associated with IR, although their effects on subsequent progression to T2D were minimal in this prospective Asian cohort.     

Increasing oxytocin receptor expression in the nucleus accumbens of pre-pubertal female prairie voles enhances alloparental responsiveness and partner preference formation as adults

Oxytocin receptors (OXTR) in the nucleus accumbens (NAcc) promote alloparental behavior and partner preference formation in female prairie voles. Within the NAcc there is significant individual variation in OXTR binding and virgin juvenile and adult females with a high density of OXTR in the NAcc display an elevated propensity to engage in alloparental behavior toward novel pups. Over-expression of OXTR in the NAcc of adult female prairie voles using viral vector gene transfer facilitates partner preference formation, but has no effect on alloparental behavior, even though OXTR antagonists infused into the NAcc blocks both behaviors. We therefore hypothesized that long-term increases in OXTR signaling during development may underlie the relationship between adult OXTR density in the NAcc and alloparental behavior. To test this hypothesis, we used viral vector gene transfer to increase OXTR density in the NAcc of prepubertal, 21 day old female prairie voles and tested for both alloparental behavior and partner preference formation as adults. Consistent with a developmental impact of OXTR signaling, adults over-expressing OXTR from weaning display both increased alloparental behavior and partner preference formation. Thus, the relatively acute impact of elevated OXTR signaling in the NAcc on partner preference formation previously reported appears to be dissociable from the effects of longer term, developmentally relevant OXTR signaling necessary for modulating alloparental behavior. These results are consistent with the hypothesis that oxytocin can have both long-term “organizational” effects as well as acute “activational” effects on affiliative behaviors.     

Factors associated with oxidative stress and cancer risk in the Breast and Prostate Cancer Cohort Consortium

Abstract

Both endogenous factors (genomic variations) and exogenous factors (environmental exposures, lifestyle) impact the balance of reactive oxygen species (ROS). Variants of the ND3 (rs2853826; G10398A) gene of the mitochondrial genome, manganese superoxide dismutase (MnSOD; rs4880 Val16Ala) and glutathione peroxidase (GPX-1; rs1050450 Pro198Leu), are purported to have functional effects on regulation of ROS balance. In this study, we examined associations of breast and prostate cancer risks and survival with these variants, and interactions between rs4880–rs1050450, and alcohol consumption—rs2853826. Nested case-control studies were conducted in the Breast and Prostate Cancer Cohort Consortium (BPC3), consisting of nine cohorts. The analyses included over 10726 post-menopausal breast and 7532 prostate cancer cases with matched controls. Logistic regression models were used to evaluate associations with risk, and proportional hazard models were used for survival outcomes. We did not observe significant interactions between polymorphisms in MnSOD and GPX-1, or between mitochondrial polymorphisms and alcohol intake and risk of either breast (p-interaction of 0.34 and 0.98, respectively) or prostate cancer (p-interaction of 0.49 and 0.50, respectively). We observed a weak inverse association between prostate cancer risk and GPX-1 Leu198Leu carriers (OR 0.87, 95% CI 0.79–0.97, p = 0.01). Overall survival among women with breast cancer was inversely associated with G10398 carriers who consumed alcohol (HR 0.66 95% CI 0.49–0.88). Given the high power in our study, it is unlikely that interactions tested have more than moderate effects on breast or prostate cancer risk. Observed associations need both further epidemiological and biological confirmation.     

Increasing oxytocin receptor expression in the nucleus accumbens of pre-pubertal female prairie voles enhances alloparental responsiveness and partner preference formation as adults

Oxytocin receptors (OXTR) in the nucleus accumbens (NAcc) promote alloparental behavior and partner preference formation in female prairie voles. Within the NAcc there is significant individual variation in OXTR binding and virgin juvenile and adult females with a high density of OXTR in the NAcc display an elevated propensity to engage in alloparental behavior toward novel pups. Over-expression of OXTR in the NAcc of adult female prairie voles using viral vector gene transfer facilitates partner preference formation, but has no effect on alloparental behavior, even though OXTR antagonists infused into the NAcc blocks both behaviors. We therefore hypothesized that long-term increases in OXTR signaling during development may underlie the relationship between adult OXTR density in the NAcc and alloparental behavior. To test this hypothesis, we used viral vector gene transfer to increase OXTR density in the NAcc of prepubertal, 21 day old female prairie voles and tested for both alloparental behavior and partner preference formation as adults. Consistent with a developmental impact of OXTR signaling, adults over-expressing OXTR from weaning display both increased alloparental behavior and partner preference formation. Thus, the relatively acute impact of elevated OXTR signaling in the NAcc on partner preference formation previously reported appears to be dissociable from the effects of longer term, developmentally relevant OXTR signaling necessary for modulating alloparental behavior. These results are consistent with the hypothesis that oxytocin can have both long-term “organizational” effects as well as acute “activational” effects on affiliative behaviors.     

Lack of association of polymorphic variants of genes encoding zinc transporters with the risk of orofacial cleft-affected pregnancies

Maternal zinc deficiency seems to be a risk factor for orofacial clefts in offspring. This study was undertaken to investigate the involvement of polymorphic variants of genes for zinc transporters in the susceptibility of clefting. PCRRFLP analysis was used to analyze single nucleotide polymorphisms of SLC30A1 (rs7526700, rs2278651, rs611386), SLC30A4 (rs2453531, rs8029246), SLC30A5 (rs351444, rs164393, rs6886492), SLC39A1 (rs10127484, rs11264736), and SLC39A3 (rs759071, rs4806874, rs10415622) in mothers of children with non-syndromic cleft lip with or without cleft palate (CL/P) and control mothers. The allele, genotype, and haplotype distribution was found to be similar among case and control mothers. Also, the gene-by-gene interaction analysis conducted using the Multifactor Dimensionality Reduction approach revealed no significant interactive genetic effect on having a child with a cleft. In conclusion, our results demonstrated that the analyzed polymorphic variants of genes for zinc transporters are not implicated in abnormal palatogenesis in the investigated group of women from the Polish population.     

Association Studies on Ghrelin and Ghrelin Receptor Gene Polymorphisms With Obesity

Ghrelin exerts a stimulatory effect on appetite and regulates energy homeostasis. Ghrelin gene variants have been shown to be associated with metabolic traits, although there is evidence suggesting linkage and association with obesity and the ghrelin receptor (GHSR). We hypothesized that these genes are good candidates for susceptibility to obesity. Direct sequencing identified 12 ghrelin single‐nucleotide polymorphisms (SNPs) and 8 GHSR SNPs. The 10 common SNPs were genotyped in 1,275 obese subjects and in 1,059 subjects from a general population cohort of European origin. In the obesity case‐control study, the GHSR SNP rs572169 was found to be associated with obesity (P = 0.007 in additive model, P = 0.001 in dominant model, odds ratio (OR) 1.73, 95% confidence interval (1.23–2.44)). The ghrelin variant, g.A265T (rs4684677), showed an association with obesity (P = 0.009, BMI adjusted for age and sex) in obese families. The ghrelin variant, g.A‐604G (rs27647), showed an association with insulin levels at 2‐h post‐oral glucose tolerance test (OGTT) (P = 0.009) in obese families. We found an association between the eating behavior “overeating” and the GHSR SNP rs2232169 (P = 0.02) in obese subjects. However, none of these associations remained significant when corrected for multiple comparisons. Replication of the nominal associations with obesity could not be confirmed in a German genome‐wide association (GWA) study for rs4684677 and rs572169 polymorphisms. Our data suggest that common polymorphisms in ghrelin and its receptor genes are not major contributors to the development of polygenic obesity, although common variants may alter body weight and eating behavior and contribute to insulin resistance, in particular in the context of early‐onset obesity.     

Lack of association of CD36 SNPs with early onset obesity: a meta-analysis in 9,973 European subjects

A recent study suggested that four CD36 polymorphisms (namely rs3211867, rs3211883, rs3211908, and rs1527483) were associated with an increased risk of obesity, an increased BMI and percentage of body fat in European adolescents. We first attempted to confirm these results in three independent case-control genome-wide association studies (GWAS) data totaling 3,509 subjects of French and German origin, but we were unable to find any association of these variants with early onset obesity risk. We then genotyped the four CD36 single-nucleotide polymorphisms (SNPs) in a large population-based study of 4,667 Finnish subjects and we did not replicate any of the recently reported associations with BMI. By combining all available data in a meta-analysis (N = 9,973), we found no evidence for an association of the reported four variants in CD36 with increased obesity risk or increased BMI (0.07 ≤ P values ≤ 0.93). Finally, we assessed the contribution of the full CD36 locus gene variation to obesity risk in 3,509 subjects and we did not detect any significant association with obesity after correction for multiple testing. In summary, we were unable to confirm the recently reported association of variants in CD36 with early onset obesity in populations of European ancestry.     

Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome‐wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European‐Americans (EA; 2927 cases) and 3132 African‐Americans (AA: 1315 cases) participating in the family‐based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h ² in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome‐wide significant (GWS; P < 5E‐08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion‐deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans‐ancestral meta‐analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward‐related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non‐European samples with distinct patterns of substance use may lead to the identification of novel ancestry‐specific genetic markers of risk.     

Effect of interleukin-17A and interleukin-17F gene polymorphisms on the risk of gastric cancer in a Chinese population

We selected six tagged single-nucleotide polymorphisms (SNPs) in the IL-17A and IL-17F genes, and evaluated the relationship between the six common SNPs and H. pylori infection, tobacco smoking and subsites of gastric cancer in gastric cancer patients. Genotyping of IL-17A (rs2275913, rs3748067 and rs3819025) and IL-17A (rs763780, rs9382084, and rs12203582) was performed in a 384-well plate format on the MassARRAY® platform. An unconditional multiple logistical regression model was performed to determine the association between IL-17A and IL-17F genetic variations and gastric cancer risk. Unconditional logistic regression analysis showed that subjects carrying the rs2275913AA and rs3748067 TT genotypes were 1.70 and 3.45 times more likely to develop gastric cancer. Furthermore, rs2275913 and rs3748067 genetic variants significantly interacted with H. pylori infection on the risk of gastric cancer. The interaction between rs3748067 and rs9382084 genetic variants and tobacco smoking trend was significant. In addition, rs2275913, rs3748067 and rs9382084 genetic variants were only associated with non-cardia gastric cancer. The findings suggest that the rs2275913, rs3748067 and rs9382084 polymorphisms increase the risk of gastric cancer, and they interact with H. pylori infection, tobacco smoking and subsites of gastric cancer. These findings could be helpful in identifying individuals at increased risk for developing gastric cancer.     

Genetic Variations in MicroRNA Processing Genes Are Associated with Susceptibility in Depression

MicroRNAs (miRNAs) are new prominent gene expression regulators that have critical roles in neural development by regulating synaptic functions, and miRNA biogenesis may play an important role in psychiatric disorders. Despite emerging evidences demonstrating that single-nucleotide polymorphisms in the miRNA processing genes were associated with cancer and cardiovascular disorders, evidences about association between variants of the genes and depression are lacking. This study aims to find the association between miRNA processing gene variants and depression. We genotyped three polymorphisms from three miRNA processing genes in a case-control study including 314 patients and 252 matched healthy controls. The high-resolution melting method was used to genotype the three loci. Frequencies of genotypes and alleles showed significant difference between patients with depression and healthy controls in DGCR8 rs3757 and AGO1 rs636832. An allele frequency was significantly higher in rs3757 and lower in rs636832, respectively. Variant allele of DGCR8 rs3757 was associated with increased risk of suicidal tendency and improvement response to antidepressant treatment, whereas the variant of AGO1 rs636832 showed decreased risk of suicidal tendency, suicidal behavior, and recurrence. Besides allele frequency showed significant difference when compared patients with remission to controls, no significant differences were found in GEMIN4 rs7813 between patients and healthy controls. DGCR8 rs3757 and AGO1 rs636832 were found to have significant association with depression, and GEMIN4 rs7813 did not affect susceptibility to depression. These observations suggested that miRNA processing polymorphisms may affect depression risk and treatment.     

Genome-wide association study on bipolar disorder in the Bulgarian population

Bipolar disorder is a severe psychiatric disorder influenced by environmental and genetic factors. Genetic studies have implicated many variants in the disease's etiology but only few have been successfully replicated. We conducted a genome-wide association study (GWAS) on bipolar disorder in the Bulgarian population followed by a replication study of the top 100 single nucleotide polymorphisms (SNPs) showing the smallest P values. The GWAS was performed on 188 bipolar disorder patients and 376 control subjects genotyped on the Illumina 550 platform. The replication study was conducted on 122 patients and 328 controls. Although our study did not show any association P value that achieved genome-wide significance, and none of the top 100 SNPs reached the Bonferroni-corrected P value in the replication study, the plausible involvement of some variants cannot be entirely discarded. Three polymorphisms, rs8099939 [P = 2.12 × 10(-6), odds ratio (OR) = 1.95, 95% confidence interval (CI) = 1.43-2.67] in GRIK5, rs6122972 (P = 3.11 × 10(-6), OR = 2.02, 95% CI = 1.46-2.80) in PARD6B and rs2289700 (P = 9.14 × 10(-6), OR = 2.13, 95% CI = 1.53-2.95) in CTSH remained associated at a similar level after Mantel-Haenszel test for combining the results from the genome-wide and replication studies. A modest association was also detected for SNP rs1012053 (GWAS P = 4.50 × 10(-2)) in DGKH, which has already been reported as the most significant variant in a previous genome-wide scan on bipolar disorder. However, further studies using larger datasets are needed to identify variants with smaller effects that contribute to the risk of bipolar disorder.     

SNPs in CHRNA6 and CHRNB3 are associated with alcohol consumption in a nationally representative sample

The CHRNA6 and CHRNB3 genes have been associated with nicotine dependence and early subjective response to nicotine. Here we present evidence, using a nationally representative sample of adults, that this region is also associated with alcohol behaviors. Six SNPs (single nucleotide polymorphisms) spanning the CHRNB3/A6 genes were analyzed using the statistical genetics software FBAT-PC, which allows one to examine a collection of multiple phenotypes to generate a maximally heritable composite phenotype for each SNP. The six SNPs were tested using FBAT-PC including four alcohol phenotypes: average number of drinks, blackouts, total number of DSM-IV abuse and dependence symptoms endorsed, and quit attempts. Three SNPs in CHRNA6 (rs1072003, P = 0.015; rs892413, P = 0.0033 and rs2304297, P = 0.012) and one SNP in CHRNB3 (rs13280604, P = 0.0053) were associated with a composite of the alcohol phenotypes. The association was primarily driven by the average number of drinks.