Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes

Smoking is a risk factor for most of the diseases leading in mortality1. We conducted genome-wide association (GWA) meta-analyses of smoking data within the ENGAGE consortium to search for common alleles associating with the number of cigarettes smoked per day (CPD) in smokers (N=31,266) and smoking initiation (N=46,481). We tested selected SNPs in a second stage (N=45,691 smokers), and assessed some in a third sample (N=9,040). Variants in three genomic regions associated with CPD (P< 5·10−8), including previously identified SNPs at 15q25 represented by rs1051730-A (0.80 CPD,P=2.4·10−69), and SNPs at 19q13 and 8p11, represented by rs4105144-C (0.39 CPD, P=2.2·10−12) and rs6474412-T (0.29 CPD,P= 1.4·10−8), respectively. Among the genes at the two novel loci, are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6), and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6) highlighted in previous studies of nicotine dependence2-3. Nominal associations with lung cancer were observed at both 8p11 (rs6474412-T,OR=1.09,P=0.04) and 19q13 (rs4105144-C,OR=1.12,P=0.0006).

To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI ¼ 0.06-0.08) mmol/l in fasting glucose levels (P ¼ 3.2 Â 10 À50 ) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P ¼ 1.1 Â 10 À15 ). The same allele was associated with an increased risk of type 2 diabetes (odds ratio ¼ 1.09 (1.05-1.12), per G allele P ¼ 3.3 Â 10 À7 ) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P ¼ 1.1 Â 10 À57 ) and GCK (rs4607517, P ¼ 1.0 Â 10 À25 ) loci.Blood and plasma fasting glucose levels are tightly regulated within a narrow physiologic range by a feedback mechanism that targets a particular fasting glucose set point for each individual 1,2 . Disruption of normal glucose homeostasis and substantial elevations of fasting glucose are hallmarks of type 2 diabetes (T2D) and typically result from sustained reduction in pancreatic beta-cell function and insulin secretion.However, even within healthy, nondiabetic populations there is substantial variation in fasting glucose levels. Approximately one-third of this variation is genetic 3 , but little of this heritability has been explained. There is growing evidence to suggest that common variants contributing to variation in fasting glucose are largely distinct from those associated with major disruptions of beta-cell function that predispose to T2D. Common sequence variants in the GCK (glucokinase) promoter 4-6 , and around genes encoding the islet-specific glucose-6-phosphatase (G6PC2) 5,6 and the glucokinase regulatory protein (GCKR) 7-9 , have each been associated with individual variation in fasting glucose levels, but have, at best, weak effects on T2D