To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 × 10 −17 ) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.Lung cancer is frequently cited as a malignancy attributable solely to environmental exposures -primarily cigarette smoke. However, evidence that genetic factors influence lung cancer © 2008 Nature Publishing Group Correspondence should be addressed to C.I.A. (E-mail: camos@mdanderson.org). 6 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS Texas: C.I.A. and M.R.S. conceived of this study. M.R.S. established the Texas lung cancer study. C.I.A. supervised and performed the analyses. G.M. provided oversight in manuscript development and in the conduct of genetic studies. I.P.G., Q.D., Q.Z., W.V.C. and X.G. performed statistical analyses. S.S. developed and implemented statistical procedures for joint analysis. X.W. and J. Direct evidence for a genetic predisposition to lung cancer is provided by the increased risk associated with constitutional TP53 (tumor protein p53) 4 and RB1 (retinoblastoma) 5,6 gene mutations, rare mendelian cancer syndromes such as Bloom's 7 and Werner's syndromes 8 , and strongly familial lung cancer 9 . The genetic basis of inherited susceptibility to lung cancer outside the context of these disorders is at present undefined, but a model in which high-risk alleles account for all of the excess familial risk seems unlikely. Alternatively, part of the inherited genetic risk may be caused by low-penetrance alleles. This hypothesis implies that testing for allelic association should be a powerful strategy for identifying alleles that predispose to lung cancer.We conducted a genome-wide association study (GWAS) of histologically confirmed nonsmall cell lung cancer (NSCLC) to identify common low-penetrance alleles influencing lung cancer risk. To minimize confounding effects from cigarette smoking and increase the power to detect genetic effects, we frequency matched controls to cases according to smoking behavior. We also matched controls to cases by age (within 5 year categories) and sex, and we further matched former smokers by year...

To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 × 10−17), 8q24.21 (rs4295627, CCDC26; P = 2.34 × 10−18), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 × 10−15), 20q13.33 (rs6010620, RTEL1; P = 2.52 × 10−12) and 11q23.3 (rs498872, PHLDB1; P = 1.07 × 10−8). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.

Crohn disease is a chronic, inflammatory disease of the gastrointestinal tract. A locus of ∼250 kb at 5q31 (IBD5) 1,2 was previously associated with susceptibility to Crohn disease, as indicated by increased prevalence of a risk haplotype of 11 single-nucleotide polymorphisms 3 among individuals with Crohn disease, but the pathogenic lesion in the region has not yet been identified. We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a G→C transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease. These variants alter transcription and transporter functions of the organic cation transporters and interact with variants in another gene associated with Crohn disease, CARD15, to increase risk of Crohn disease. These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease.By resequencing the five genes in the IBD5 interval, we identified ten new single-nucleotide polymorphisms (SNPs; Supplementary Table 1 online), including two in the organic cation transporter (OCTN) gene cluster (SLC22A4 and SLC22A5, encoding OCTN1 and OCTN2, respectively) that are predicted to have functional effects. The first is a C→T substitution in SLC22A4 exon 9 (1672C→T; numbered according to the cDNA sequence for SLC22A4 in GenBank) that causes the amino acid substitution L503F. Leucine or isoleucine is conserved at this position in most OCTNs and other related transporters 4 (Fig. 1a), and its substitution with phenylalanine is predicted computationally (by PolyPhen 5 , TMHMM2 (ref. 6) and PHAT transmembrane database 7 ) to be nonconservative. The second SNP is a G→C transversion in the SLC22A5 promoter (-207G→C), which disrupts a heat shock element (HSE) 207 bp upstream of the start codon (Fig. 1b).1672C→T and -207G→C are in strong linkage disequilibrium and create a two-allele risk haplotype (TC) enriched in individuals with Crohn disease (frequency = 0.54 in affected individuals versus 0.42 in controls, P = 0.0003;

We conducted a genome-wide association (GWA) study of lung cancer comparing 511,919 SNP genotypes in 1,952 cases and 1,438 controls. The most significant association was attained at 15q25.1 (rs8042374; P = 7.75 × 10 −12 ), confirming recent observations. Pooling data with two other GWA studies (5,095 cases, 5,200 controls) and with replication in an additional 2,484 cases and 3,036 controls, we identified two newly associated risk loci mapping to 6p21.33 (rs3117582, BAT3-MSH5; P combined = 4.97 × 10 −10 ) and 5p15.33 (rs401681, CLPTM1L; P combined = 7.90 × 10 −9 ). Support for inherited genetic susceptibility to lung cancer has recently come from genomewide association studies that have demonstrated that 15q25.1 variation influences lung cancer risk 1-3 .To identify risk variants for lung cancer, we carried out a GWA study. Using Illumina HumanHap550 BeadChips, we genotyped 561,466 SNPs in 1,978 cases (Supplementary Methods online). After application of quality control criteria, genotypes were available for 1,952 cases. We were able to satisfactorily genotype 552,947 SNPs (98.5%) with mean sample call rate 99.7%. For controls, we used publicly accessible HumanHap550 genotype data in 1,438 individuals from the 1958 Birth Cohort 4 (Supplementary Methods). Genotypes were available for 541,327 SNPs (97.5% of 555,352 SNPs typed) and 524,714 SNPs were common to cases and controls. Applying quality control filters, we excluded 8,534 SNPs monomorphic in either cases or controls; 2,744 with call rates < 95%; 770 showing departure from HardyWeinberg equilibrium (HWE; P < 10 −5 in cases or controls) and 747 with minor allele frequency (MAF) <1% in cases or controls; leaving 511,919 informative SNPs for analysis.

Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD). We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

BACKGROUND-Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown.

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3×10−64) and lower levels of eicosapentaenoic acid (EPA, p = 5×10−58) and docosapentaenoic acid (DPA, p = 4×10−154). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2×10−12) and DPA (p = 1×10−43) and lower docosahexaenoic acid (DHA, p = 1×10−15). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1×10−8). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

Background Omega-6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs. Methods and Results To elucidate undiscovered biologic pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with five plasma n6 PUFAs in 8,631 Caucasian adults (55% female) across five prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-gamma-linoleic acid (DGLA), arachidonic acid (AA), and adrenic acid (AdrA) were expressed as % of total fatty acids. We performed linear regression with robust standard errors to test for SNP-fatty acid associations, with pooling using inverse-variance weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118, p-value = 8.1x10−9; near NRBF2); on chromosome 16 with LA, GLA, DGLA, and AA ( rs16966952, p-value = 1.2×10−15, 5.0×10−11, 7.6×10−65, and 2.4×10−10, respectively; NTAN1); and on chromosome 6 with AdrA following adjustment for AA (rs3134950, p-value = 2.1×10−10; AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and AA, and further observed novel genome-wide significant association of this cluster with GLA, DGLA, and AdrA (p-value = 2.3×10−72, 2.6×10−151, and 6.3×10−140, respectively). Conclusions Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.