ABSTRACT
Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 × 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/genetics , Tobacco Use Disorder/genetics , Adult , Black or African American/genetics , Aged , Alleles , Black People/genetics , DNA (Cytosine-5-)-Methyltransferases/physiology , Female , Gene Frequency/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci/genetics , Smoking/genetics , White People/genetics , DNA Methyltransferase 3BABSTRACT
We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.
Subject(s)
Receptors, Nicotinic/genetics , Tobacco Use Disorder/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Polymorphism, Single Nucleotide , RNA Splice Sites , White People/geneticsABSTRACT
This article describes a mathematical model that takes an existing food intake pattern and develops a new pattern that meets a specified set of nutrition recommendations with the minimum change possible. The model examines multiple recommendations simultaneously and considers foods as they are currently eaten, so it can provide practitioners with new insights about strategies for implementing recommendations. The model shows serving units per day by food group in both existing and new intake patterns and the recommendations responsible for changes. Recommendations of the National Research Council are used, and sodium-restricted (< or = 2,400 mg) and sodium-unrestricted patterns are compared. Food intake data are from 915 nonpregnant, nonlactating women 19 to 50 years old who participated in the US Department of Agriculture's 1985 Continuing Survey of Food Intake by Individuals. The sodium-restricted pattern contains proportionately more dairy products, fruit, and red meat and proportionately less grain products, fish, and vegetables than the unrestricted-sodium pattern. Nutrition recommendations responsible for changes in the existing pattern include those for saturated fatty acids (< 10% kcal), carbohydrate (> or = 55% kcal), zinc (100% of Recommended Dietary Allowance [RDA]), potassium (> or = 3,500 mg/day), and vitamin E (100% RDA), in addition to sodium. Implications of the sodium recommendation for food selection and preparation, especially of food mixtures and commercially prepared products, are discussed.
