Showing papers by "Thorgeir E. Thorgeirsson published in 2010"

Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.

Abstract: Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).

A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.

Abstract: Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.

Addictions and their familiality in Iceland.

Abstract: Here, we provide an overview of previous family studies of addiction and present a new family study based on clinical data for more than 19,000 individuals who have been treated for addiction in Iceland over the last three decades. Coupled with the extensive Icelandic genealogy information, this population-based sample provides a unique opportunity for family studies. The relative risk (RR) was determined for up to fifth-degree relatives of probands diagnosed with alcohol, cannabis, sedative, and amphetamine dependence. We observe highly significant RR values for all substances ranging from 2.27 for alcohol to 7.3 for amphetamine, for first-degree relatives, and RRs significantly above 1 for distant relations, where the effect of shared environmental factors is minimized. The magnitude of risk in psychostimulant dependence is particularly striking. These findings emphasize the role of genetics in the etiology of addiction and highlight the importance of substance-specific effects.

GPC5 rs2352028 variant and risk of lung cancer in never smokers

Abstract: We read with great interest the genome-wide association study (GWAS) of Li et al1 in the April, 2010 issue of The Lancet Oncology, reporting an association (OR=1·46, 95%CI=1·26–1·70) between the single nucleotide polymorphism rs2352028 mapping to chromosome 13q31·3 and lung cancer risk in never smokers We sought to replicate this finding using data from seven GWAS of lung cancer in Caucasian populations,2–5 with rs2352028 genotype data on 754 never smoker lung cancer cases and 10,580 controls None of the seven studies provided statistically significant evidence for an association between rs2352028 and lung cancer risk in never smokers, even when combined (P=0·57, under both fixed and random effects models; Cochran’s Q Pheterogeneity=0·62, Figure 1), although we had >90% statistical power to detect an association with rs2352028 of 1·26 (the lower limit of the 95% CI reported by Li et al) at the 5% significance level Moreover, the association was not significant in the overall meta-analysis pooling results from our seven studies and from Li et al (OR=1·10, P=0·25, under random effects model; Pheterogeneity=0·003) Analyses using other genetic models (Supplemental Figure 1); adjusting for additional potential confounders, including history of COPD, exposure to second-hand smoke and family history of lung cancer (EAGLE2 only, OR=0·86; 96% CI = 0·63–1·19, p=0·37); or restricted to adenocarcinomas (Figure 1) also provided no evidence for a significant relationship Of note, all controls in our analyses were never smokers, with the exception of the UK sample for which we had no smoking information However, the frequency of the rs2352028 T allele was not significantly different between ever smokers (19,656) and never smokers (7,453) (OR=1·04, p-value=0·30) from other groups, thus the results are not likely to be affected by smoking status in controls Figure 1 Association between rs2352028 and lung cancer risk overall and in adenocarcinoma only in never smokers (additive genetic model) Results from seven independent studies and overall meta-analysis including results from the new seven independent studies The Li et al GWAS was based on 888 cases and 1,384 controls and the association between rs2352028 and lung cancer was at P-value=5·94×10−6 While nominally significant, it is well recognized that as GWAS involve many markers, numerous false positive associations will inevitably be generated, with only a small number being truly associated with disease susceptibility Hence, associations require a high level of statistical significance (5·0×10−7–5·0×10−8) to be established beyond reasonable doubt, and the reported association does not attain genome-wide significance Moreover, under a random effects model the association between rs2352028 and lung cancer reported by Li et al is weak (P=0·0027 overall and P=0·034 for adenocarcinomas) The significant heterogeneity between our studies and those from Li et al could be due to genuine differences in underlying population characteristics and/or due to “winner’s curse” associated with a chance finding Li et al reported a relationship between GPC5 expression in 70 non-tumor lung tissue samples and rs2352028 genotype We examined this correlation in fresh frozen lung tissue samples from 45 adenocarcinomas and 37 non-tumor samples6 and in blood samples from 62 adenocarcinoma cases and 77 controls Although we found lower expression levels in tumor tissue vs noninvolved tissue as previously reported1, we found no significant correlation of rs2352028 genotypes with GPC5 expression in the lung tumor and non-involved tissue samples from cases and in blood samples from controls (p-values=0·07, 0·32 and 0·41, respectively) We observed an association (p=0·03) between genotype and GPC5 expression in blood samples from adenocarcinoma cases, although no trend was apparent and no difference in GPC5 expression between cases and controls was observed (Supplemental Figure 2) This work highlights the importance of large sample sizes and the need for replication in multiple independent groups to identify true positive associations