Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer

Byun, Jinyoung; Han, Younghun; Li, Yafang; Xia, Jun; Long, Erping; Choi, Jiyeon; Xiao, Xiangjun; Zhu, Meng; Zhou, Wen; Sun, Ryan; Bossé, Yohan; Song, Zhuoyi; Schwartz, Ann G.; Lusk, Christine M.; Rafnar, Thorunn; Stefánsson, Kári; Zhang, Tongwu; Wei, Zhao; Pettit, Rowland W.; Liu, Yanhong; Li, Xihao; Zhou, Hufeng; Walsh, Kyle M.; Gorlov, Ivan P.; Gorlova, Olga Y.; Zhu, Dakai; Rosenberg, Susan M.; Pinney, Susan M.; Bailey-Wilson, Joan E.; Mandal, Diptasri; Andrade, Mariza de; Gaba, Colette; Willey, James C.; You, Ming; Anderson, Marshall W.; Wiencke, John K.; Albanês, Demetrius; Lam, Stephan; Tardón, Adonina; Chen, Chu; Goodman, Gary E.; Bojesen, Stig E.; Brenner, Hermann; Landi, Maria Teresa; Chanock, Stephen J.; Johansson, Mattias; Muley, Thomas; Risch, Angela; Wichmann, H‐Erich; Bickeböller, Heike; Christiani, David C.; Rennert, Gad; Arnold, Susanne M.; Field, John K.; Shete, Sanjay; Marchand, Loı̈c Le; Melander, Olle; Brunnström, Hans; Liu, Geoffrey; Andrew, Angeline S.; Kiemeney, Lambertus A.; Shen, Hongbing; Zienolddiny, Shanbeh; Grankvist, Kjell; Johansson, Mikael; Caporaso, Neil E.; Cox, Angela; Hong, Yun-Chul; Yuan, Jian‐Min; Lazarus, Philip; Schabath, Matthew B.; Aldrich, Melinda C.; Patel, Alpa V.; Lan, Qing; Rothman, Nathaniel; Taylor, Fiona; Kachuri, Linda; Witte, John S.; Sakoda, Lori C.; Spitz, Margaret R.; Brennan, Paul; Lin, Xihong; McKay, James; Hung, Rayjean J.; Amos, Christopher I.

doi:10.1038/s41588-022-01115-x

Cited by 60 publications

(50 citation statements)

References 97 publications

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“…Thus, the impact of BMI on the incidence of lung cancer histologic types and the underlying mechanisms warrants further investigation. The latest lung cancer genome-wide association studies identified distinct genetic variants for different lung histologic types [38,39]. For example, the identified variants specifically for lung adenocarcinoma are near genes related to lung function, telomere regulation and endogenous DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Body mass index and incidence of lung cancer in the HUNT study: using observational and Mendelian randomization approaches

et al. 2022

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Background Traditional observational studies have shown an inverse association between body mass index (BMI) and lung cancer risk. Mendelian randomization (MR) analysis using genetic variants as instruments for BMI may clarify the nature of the association. Aims We studied the causal association between BMI and lung cancer incidence using observational and MR approaches. Methods We followed up 62,453 cancer-free Norwegian adults from 1995–97 (HUNT2) until 2017. BMI at baseline in HUNT2 was classified as < 25.0, 25.0–29.9 and ≥ 30.0 kg/m2. BMI change over ten years between HUNT1 (1984–86) and HUNT2 was calculated and classified into quartiles. Seventy-five genetic variants were included as instruments for BMI (among which 14 also associated with smoking behavior). Incident lung cancer cases were ascertained from the Cancer Registry of Norway. Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Multivariable MR was used to examine the effect of BMI after genetically controlling for smoking. Results During a median follow-up of 21.1 years, 1009 participants developed lung cancer including 327 with lung adenocarcinoma. The HRs and 95% CIs for incidence of adenocarcinoma were 0.73 (0.58–0.92) for BMI 25.0–29.9 kg/m2 and 0.53 (0.37–0.76) for BMI ≥ 30 kg/m2 compared with BMI < 25.0 kg/m2 in HUNT2 (P for trend < 0.001). However, there was little evidence of a dose–response relationship between the BMI change from HUNT1 to HUNT2 in quartiles and the incidence of adenocarcinoma (P for trend = 0.08). Furthermore, multivariable MR approach suggested a positive association between genetically determined 1 kg/m2 increase in BMI and the incidence of adenocarcinoma (HR 1.25, 95% CI 1.02–1.53). No associations were found with other lung cancer histologic types. Conclusions Our study suggests that the inverse association between baseline BMI and lung adenocarcinoma in observational analysis may not be causal. More MR studies are needed to confirm our finding of a positive association between BMI and lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Body mass index and incidence of lung cancer in the HUNT study: using observational and Mendelian randomization approaches

et al. 2022

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“…Based on the cross-ancestry genome-wide meta-analysis, 35 significant SNPs (p <5∗10 −8 for European ancestry populations) in linkage disequilibrium (LD; r 2 >0.1), the SNP with the lowest p value was included in the PRS. Finally, we used 23 SNPs to calculate the lung cancer PRS based on the following equation:

where M denotes the total number of SNPs, and β j represents the per-allele log odds ratio (OR) for lung cancer associated with SNP j , which is reported by the previous GWAS.…”

Section: Methodsmentioning

confidence: 99%

“…Finally, we used 23 SNPs to calculate the lung cancer PRS based on the following equation:

where M denotes the total number of SNPs, and β j represents the per-allele log odds ratio (OR) for lung cancer associated with SNP j , which is reported by the previous GWAS. 35 …”

Section: Methodsmentioning

confidence: 99%

Association between biological aging and lung cancer risk: Cohort study and Mendelian randomization analysis

Ma¹,

Chen²,

Wang³

et al. 2023

iScience

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“…Previous GWAS suggested that the T allele is additionally associated with decreased parental lifespan 27 and increased risk of multiple cancers such as melanoma 28 and lung cancer 29 . This variant is also associated with multi-context, multi-eGene (IRF4 and EXOC2), and discordant cis-regulatory events.…”

Section: Potential Molecular Mechanismsmentioning

confidence: 99%

“…Specifically, the T allele is correlated with higher IRF4 expressions in the lung and whole blood but lower IRF4 expression in skin tissues. Higher IRF4 expressions in the human lung were reported to promote endogenous DNA damage in lung fibroblasts 29 . Another antagonistically pleiotropic variant-rs34811474 at chromosome 4p15.2-has its reproductionenhancing G allele associated with an increased risk of osteoarthritis, an age-related degenerative disease 30 .…”

Section: Potential Molecular Mechanismsmentioning

confidence: 99%

Evidence for the role of selection for reproductively advantageous alleles in human aging

Long

Zhang

2023

Preprint

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The antagonistic pleiotropy hypothesis posits that natural selection for pleiotropic mutations that confer earlier or more reproduction but impair the post-reproductive life causes aging. This hypothesis of the evolutionary origin of aging is supported by case studies but lacks unambiguous genomic evidence. Here we genomically test this hypothesis using the genotypes, reproductive phenotypes, and death registry of 276,406 UK Biobank participants. We observe a strong, negative genetic correlation between reproductive traits and lifespan. Individuals with higher polygenetic scores for reproduction (PGSR) have lower survivorships to age 76 (SV76), andPGSRincreased over birth cohorts from 1940 to 1969. Similar trends are found from individual genetic variants examined.PGSRandSV76remain negatively correlated upon the control of the offspring number, revealing horizontal pleiotropy between reproduction and lifespan. Intriguingly, regardless ofPGSR, having two children maximizesSV76. These and other findings strongly support the antagonistic pleiotropy hypothesis of aging in humans.

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Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer

Cited by 60 publications

References 97 publications

Body mass index and incidence of lung cancer in the HUNT study: using observational and Mendelian randomization approaches

Body mass index and incidence of lung cancer in the HUNT study: using observational and Mendelian randomization approaches

Association between biological aging and lung cancer risk: Cohort study and Mendelian randomization analysis

Evidence for the role of selection for reproductively advantageous alleles in human aging

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