Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.

• MeSH
• adenokarcinom genetika   patologie   MeSH
• Bayesova věta MeSH
• celogenomová asociační studie MeSH
• genetická predispozice k nemoci MeSH
• lidé MeSH
• nádory plic genetika   patologie   MeSH
• spinocelulární karcinom genetika   patologie   MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

OBJECTIVE: To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences. DESIGN: Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US. SETTING: General population. PARTICIPANTS: 26,018 men and women aged 50-79 years. MAIN OUTCOME MEASURES: All-cause, cardiovascular, and cancer mortality. RESULTS: 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses. CONCLUSIONS: Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.

• MeSH
• kardiovaskulární nemoci krev   mortalita   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory krev   mortalita   MeSH
• nedostatek vitaminu D komplikace   mortalita   MeSH
• roční období MeSH
• senioři MeSH
• sexuální faktory MeSH
• věkové faktory MeSH
• vitamin D analogy a deriváty   krev   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Evropa MeSH
• Spojené státy americké MeSH

We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.

• MeSH
• adenokarcinom genetika   MeSH
• celogenomová asociační studie MeSH
• checkpoint kinasa 2 genetika   MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• metaanalýza jako téma MeSH
• nádory plic genetika   MeSH
• prognóza MeSH
• protein BRCA2 genetika   MeSH
• rizikové faktory MeSH
• spinocelulární karcinom genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH

• MeSH
• chronická renální insuficience etiologie   MeSH
• eliminace ledvinami MeSH
• hodnoty glomerulární filtrace * MeSH
• johexol analýza   MeSH
• kohortové studie MeSH
• krevní glukóza * analýza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• průřezové studie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

• MeSH
• dospělí MeSH
• infarkt myokardu diagnóza   etiologie   mortalita   MeSH
• kouření MeSH
• krevní tlak MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• přehledy MeSH
• srovnávací studie MeSH
• Geografické názvy
• Norsko MeSH