Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population

Zanetti, Krista A.; Wang, Zhaoming; Aldrich, Melinda C.; Amos, Christopher I.; Blot, William J.; Bowman, Elise D.; Burdette, Laurie; Cai, Qiuyin; Caporaso, Neil E.; Chung, Charles C.; Gillanders, Elizabeth M.; Haiman, Christopher A.; Hansen, Helen M.; Henderson, Brian E.; Kolonel, Laurence N.; Marchand, Loı̈c Le; Li, Shengchao; McNeill, Lorna H.; Ryan, Bríd M.; Schwartz, Ann G.; Sison, Jennette D.; Spitz, Margaret R.; Tucker, Margaret A.; Wenzlaff, Angela S.; Wiencke, John K.; Wilkens, Lynne R.; Wrensch, Margaret; Wu, Xifeng; Wang, Zheng; Zhou, Weiyin; Christiani, David C.; Palmer, Julie R.; Penning, T.M.; Rieber, Alyssa G.; Rosenberg, Lynn; Ruiz-Narváez, Edward A.; Li, Su; Vachani, Anil; Wei, Yongyue; Whitehead, Alexander S.; Chanock, Stephen J.; Harris, Curtis C.

doi:10.1016/j.lungcan.2016.05.008

Cited by 55 publications

(48 citation statements)

References 69 publications

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“…The present analysis sought to identify cross-cancer pleiotropic genetic associations for lung cancer risk in African Americans. The two most significant associations were on chromosome 15q25.1 and 5p15.33, both of which have been previously associated with lung cancer in African Americans (37)(38)(39) and recently validated in a non-independent African American consortium study (22) that included cases and controls utilized in the present study.…”

Section: Discussionsupporting

confidence: 51%

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Cross-cancer pleiotropic associations with lung cancer risk in African Americans

Jones

Bradford

Amos

et al. 2018

Preprint

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Background:Identifying genetic variants with pleiotropic associations across multiple cancers can reveal shared biologic pathways. Prior pleiotropic studies have primarily focused on European descent individuals. Yet population-specific genetic variation can occur and potential pleiotropic associations among diverse racial/ethnic populations could be missed. We examined crosscancer pleiotropic associations with lung cancer risk in African Americans. Methods:We conducted a pleiotropic analysis among 1,410 African American lung cancer cases and 2,843 controls. We examined 36,958 variants previously associated (or in linkage disequilibrium) with cancer in prior genome-wide association studies. Logistic regression analyses were conducted, adjusting for age, sex, global ancestry, study site, and smoking status. Results:We identified three novel genomic regions significantly associated (FDR-corrected pvalue < 0.10) with lung cancer risk (rs336958 on 5q14.3, rs7186207 on 16q22.2, and rs11658063 on 17q12). On chromosome16q22.2, rs7186207 was significantly associated with increased risk (OR=1.24, 95% CI: 1.12-1.38) and functional annotation using GTEx showed rs7186207 modifies DHODH gene expression. The risk allele at rs336958 on 5q14.3 was associated with reduced lung cancer risk (OR=0.68, 95% CI: 0.56-0.82), while the risk allele at rs11658063 on 17q12 was associated with increased risk (OR=1.24, 95% CI: 1.11-1.39). Conclusion:We identified novel associations on chromosomes 5q14.3, 16q22.2, and 17q12, which contain HNF1B, DHODH, and HAPLN1 genes, respectively. SNPs within these regions have been previously associated with multiple cancers. This is the first study to examine cross-cancer pleiotropic associations for lung cancer in African Americans. Impact:Our findings demonstrate novel cross-cancer pleiotropic associations with lung cancer risk in African Americans.

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Section: Discussionsupporting

confidence: 51%

“…African American lung cancer cases and controls were selected from five study sites: the Epidemiology Study. A detailed description of each study has been previously reported (22). All studies were approved by the Institutional Review Board at each institution and written informed consent was obtained from all participants.…”

Section: Study Populationmentioning

confidence: 99%

Cross-cancer pleiotropic associations with lung cancer risk in African Americans

Jones

Bradford

Amos

et al. 2018

Preprint

Self Cite

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“…In LUSC subgroup, this risk signal was not observed. Previous studies have proved that rs2736100 showed more significant association with LUAD than with LUSC . Therefore, different effect size of variants in TERT and relative small sample size of LUSC could account for this.…”

Section: Discussionmentioning

confidence: 95%

“…Previous studies have proved that rs2736100 showed more significant association with LUAD than with LUSC. 39,40 Therefore, different effect size of variants The potential functional disease-causing SNPs were in bold. This table just showed the results of SNPs located in promoter region or mentioned in the article.…”

Section: Discussionmentioning

confidence: 99%

Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

Fan

et al. 2018

Molecular Carcinogenesis

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Genome-wide association studies (GWAS) and fine mapping studies have identified multiple lung cancer susceptibility variants in TERT-CLPTM1L region. However, it is still unclear about the relationship between these risk variants and the independent lung cancer risk signals in this region. Therefore, we evaluated the independent susceptibility signals for lung cancer and explored the potential functional variants in this region. Sequential conditional analysis was used to detect the independent susceptibility loci based on four lung cancer GWAS datasets with 12 843 lung cases and 12 639 controls. Comprehensively functional annotations were performed for each independent signal. Three independent susceptibility signals were identified in multi-ethnic population. For the first signal, rs2736100 showed the most significant association with lung cancer risk (C > A, OR = 0.82, 95%CI: 0.79-0.85, P = 1.98 × 10 ). Rs36019446 was the top-ranked site (A > G, OR = 0.88, 95%CI: 0.84-0.92, P = 1.74 × 10 ) in the second signal. For the third signal, rs326048 was the leading SNP (A > G, OR = 0.91, 95%CI: 0.87-0.95, P = 1.38 × 10 ). The following subgroup analysis found the same three loci among Asian population. Further, we compared the difference between various subgroup populations. Functional annotations revealed that rs2736100, rs27996 (r = 0.85 with rs36019446) and rs326049 (r = 0.73 with rs326048) could be potential functional variants in these three risk signals, respectively. In conclusion, although multiple variants have been found associated with lung cancer risk in TERT-CLPTM1L region, our findings indicated that there are three independent lung cancer susceptibility signals in this region.

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“…An additional UK Biobank GWAS study (n~458,000) identified an intronic DCC SNP, rs12970816, associated with cigarette smoking status [83]. Finally, one more study (discovery: n = 5339, replication: n = 1682) reported that the intronic DCC SNP, rs1372626, while not genome-wide significant, was the SNP most strongly associated with cigarette smoking, and was plausibly underpowered [84].…”

Section: Haploinsufficiency: Personality Traits and Drugrelated Bmentioning

confidence: 99%

The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

2019

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Axon guidance molecules direct growing axons toward their targets, assembling the intricate wiring of the nervous system. One of these molecules, Netrin-1, and its receptor, DCC (deleted in colorectal cancer), has profound effects, in laboratory animals, on the adolescent expansion of mesocorticolimbic pathways, particularly dopamine. Now, a rapidly growing literature suggests that (1) these same alterations could occur in humans, and (2) genetic variants in Netrin-1 and DCC are associated with depression, schizophrenia, and substance use. Together, these findings provide compelling evidence that Netrin-1 and DCC influence mesocorticolimbic-related psychopathological states that emerge during adolescence.

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Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population

Cited by 55 publications

References 69 publications

Cross-cancer pleiotropic associations with lung cancer risk in African Americans

Cross-cancer pleiotropic associations with lung cancer risk in African Americans

Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

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