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Genome-wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk.

ABSTRACT: Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10?×?10^-8 ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25?×?10^-7 ; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83?×?10^-7 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64?×?10^-8 ). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.

SUBMITTER: Dai J

PROVIDER: S-EPMC7101262 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Genome-wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk.

Dai Juncheng J Huang Mingtao M Amos Christopher I CI Hung Rayjean J RJ Tardon Adonina A Andrew Angeline A Chen Chu C Christiani David C DC Albanes Demetrius D Rennert Gadi G Fan Jingyi J Goodman Gary G Liu Geoffrey G Field John K JK Grankvist Kjell K Kiemeney Lambertus A LA Le Marchand Loic L Schabath Matthew B MB Johansson Mattias M Aldrich Melinda C MC Johansson Mikael M Caporaso Neil N Lazarus Philip P Lam Stephan S Bojesen Stig E SE Arnold Susanne S Landi Maria Teresa MT Risch Angela A Wichmann H-Erich HE Bickeboller Heike H Brennan Paul P Shete Sanjay S Melander Olle O Brunnstrom Hans H Zienolddiny Shan S Woll Penella P Stevens Victoria V Hu Zhibin Z Shen Hongbing H

International journal of cancer 20191031 10

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta- ...[more]

PMID: 31577861

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Project description:Background & aimsA genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease.MethodsWe obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls.ResultsWe observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse.ConclusionsIn this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.

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Genome-wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk.

Publications

Genome-wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk.

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