Heavy smoking is a strong predictor of nicotine dependence, which is a major impediment to smoking cessation. Although both
heavy smoking and nicotine dependence are highly heritable, previous ...attempts to identify genes influencing these phenotypes
have been largely unsuccessful until very recently. We studied 1,452 heavy smokers (defined as smoking at least 30 cigarettes
per day for at least 5 years) and 1,395 light smokers (defined as smoking <5 cigarettes per day for at least 1 year) to investigate
the association of common variants in nicotinic receptor subunit genes with smoking behavior. Compared with the most common
allele, two separate groups of single nucleotide polymorphisms (SNP) in the CHRNA5-CHRNA3-CHRNB4 gene cluster were associated with heavy smoking with a very high statistical significance. One group of eight SNPs, which
included a nonsynonymous SNP in the CHRNA5 gene, was in strong linkage disequilibrium and associated with increased risk of heavy smoking. A second group of SNPs not
strongly correlated with the first was associated with decreased risk of heavy smoking. Analyses that combined both groups
of SNPs found associations with heavy smoking that varied by >2-fold. Our findings identify two loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster that predict smoking behavior and provide strong evidence for the involvement of the α5 nicotinic receptor in
heavy smoking. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3517–25)
genome-wide association study of alcohol dependence Bierut, Laura J; Agrawal, Arpana; Bucholz, Kathleen K ...
Proceedings of the National Academy of Sciences - PNAS,
03/2010, Volume:
107, Issue:
11
Journal Article
Peer reviewed
Open access
Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol ...dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10⁻⁵, but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor α2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.
Objective:
A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change ...in the 5 nicotinic cholinergic receptor (
CHRNA5
). The purpose of this study was to replicate these findings in an independent data set and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors,
CHRNA5-CHRNA3-CHRNB4
, and the risk of smoking.
Method:
Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid variant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influences receptor function.
Results:
A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across nonhuman species, but its frequency varied across human populations (0% in African populations to 37% in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown.
Conclusions:
This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.
Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and ...analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the β3 nicotinic receptor subunit gene (P = 9.4 × 10−5). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the α5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 × 10−4). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.
Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine ...dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample (N = 710) and in a European-American sample (N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects P = 4.49 x 10(-8); odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25-1.61 as well as in African-Americans only (P = 0.015; OR, 2.04; 1.15-3.62) and in European-Americans only (P = 4.14 x 10(-7); OR, 1.40; 1.23-1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency <or= 5%) are also associated with nicotine dependence. In summary, multiple variants in this gene cluster contribute to nicotine dependence risk, and some are also associated with functional effects on CHRNA5. The nonsynonymous SNP rs16969968, a known risk variant in populations of European-descent, is also significantly associated with risk in African-Americans. Additional SNPs contribute to risk in distinct ways in these two populations.
OBJECTIVETo study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of ...nicotine metabolism.
METHODSThe conversion of deuterated (D2)-nicotine to D2-cotinine was quantified in 189 European–Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, (i) single time point measures of D2-cotinine/(D2-cotinine+D2-nicotine) after oral administration were used as a metric of CYP2A6 activity; (ii) the impact of CYP2A6 haplotype was treated as acting multiplicatively; (iii) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and (iv) a minimum number of predictive polymorphisms were justified to be included in the model based on statistical evidence of differences between haplotypes.
RESULTSThe final model includes seven polymorphisms and fits the phenotype, 30-min after D2-nicotine oral administration, with R=0.719. The predictive power of the model is robustparameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R=0.758 and vice versa with R=0.617; estimates calculated in current smokers (n=102) predict the phenotype in former-smokers (n=86) with R=0.690 and vice versa with R=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss-of-function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5′-untranslated region conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype, modest associations were found between increased metabolism and both female sex (P=4.8×10) and current smoking (P=0.02).
CONCLUSIONAmong European–Americans, seven polymorphisms in the CYP2A6 gene explain the majority of variability in the metabolism of nicotine to cotinine after oral administration. Parameters determined from this in-vivo experiment can be used to predict nicotine metabolism based on CYP2A6 genotype.
Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent ...alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (
N
= 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case–control sample (
N
= 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (
p
= 2.1 × 10
−6
) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (
p
= 7.1 × 10
−7
), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the
LMO1
(
p
= 7.2 × 10
−7
) and
PLCL1
genes (
p
= 4.1 × 10
−6
) with maxdrinks. A variant in
AUTS2
and variants in
INADL
,
C15orf32
and
HIP1
that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (
p
≤ 10
−4
) far more showed the same direction of effect in the other dataset than would be expected by chance (
p
= 2 × 10
−3
, 3 × 10
−6
), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.
Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural ...variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million single nucleotide polymorphisms (SNPs) was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31 960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with P-values less than 10−4 (minimum P-value 1.53 × 10−6). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the β3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.
Objective
Familial autosomal dominant frontotemporal dementia with ubiquitin‐positive, tau‐negative inclusions in the brain linked to 17q21‐22 recently has been reported to carry null mutations in ...the progranulin gene (PGRN). Hereditary dysphasic disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene. Longitudinal follow‐up has enabled us to identify new cases and to further characterize the dementia in this family. The goals of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree, and to assess the neuropathological characteristics using immunohistochemical techniques.
Methods
In this study we describe a detailed clinical, pathological and mutation analysis of the HDDD2 kindred.
Results
Neuropathologically, HDDD2 represents a familial frontotemporal lobar degeneration with ubiquitin‐positive, tau‐negative inclusions (FTLD‐U). We developed research classification criteria and identified three distinct diagnostic thresholds, which helped localize the disease locus. The chromosomal region with the strongest evidence of linkage lies within the minimum critical region for FTLD‐U. Sequencing of each exon of the PGRN gene led to the identification of a novel missense mutation, Ala‐9 Asp, within the signal peptide.
Interpretation
HDDD2 is an FTLD‐U caused by a missense mutation in the PGRN gene that cosegregates with the disease and with the disease haplotype in at‐risk individuals. This mutation is the first reported pathogenic missense mutation in the signal peptide of the PGRN gene causing FTLD‐U. In light of the previous reports of null mutations and its position in the gene, two possible pathological mechanisms are proposed: (1) the protein may accumulate within the endoplasmic reticulum due to inefficient secretion; and (2) mutant RNA may have a lower expression because of degradation via nonsense‐mediated decay. Ann Neurol 2006;60:314–322
PDF
