Smoking causes most lung cancer and quitting helps at any age — neither fact depends on a genotype. The interesting genetics is one locus in the nicotine receptor cluster, and an argument from 2008 about whether it acts through smoking or through the lung that has never been fully settled.
Solid lines are connections this site curates. Dashed lines mean the two ends share a research paper — worth knowing, and not a claim that one explains the other.
Start with the part that is not in doubt. Smoking causes the large majority of lung cancer; the risk falls after quitting and keeps falling for years; and nothing on this page changes either statement or should be read as softening it.
rs8034191 sits at chromosome 15q25, inside a cluster of genes for nicotinic acetylcholine receptor subunits — CHRNA5, CHRNA3 and CHRNB4. If that sounds familiar it is because the same cluster carries rs1051730, the strongest common variant for how much a person smokes, which this site covers on its smoking behaviour page.
The lung cancer association is not small by GWAS standards. It was found in about 2,000 cases and 2,600 controls, replicated across five further studies, and reached a combined p-value of 5 x 10-20. The authors estimated the locus accounts for 14% of lung cancer cases at the population level — an attributable risk, not a personal one.
Two papers reported this region in Nature in the same month of 2008, and they framed it differently.
The first observed that the risk looked statistically similar whether or not people smoked, and pointed out that these receptor subunits are expressed in lung tissue itself — alveolar epithelial cells, pulmonary neuroendocrine cells, lung cancer cell lines — and that they bind compounds found in tobacco smoke. On that reading the variant does something in the lung, not only in the brain.
The second found the same cluster affecting cigarettes smoked per day and nicotine dependence, and conferring risk of lung cancer and peripheral arterial disease. Its authors described the finding as a case study of gene-environment interaction: the variant changes how much a person smokes, and smoking does the damage.
Both papers are real, both were large, and the disagreement is about mechanism rather than about whether the association exists. Nearly two decades on, the honest summary is that some of the effect runs through smoking quantity and it is still argued how much is left over. A page that picked a side here would be telling you more than anybody knows.
A 2017 analysis of 29,266 cases and 56,450 controls found 18 susceptibility loci, ten of them new — and the most useful thing in it is that the loci are not the same for different kinds of lung cancer. Four were associated with lung cancer overall and six specifically with adenocarcinoma, the subtype that occurs most often in people who never smoked. Other loci sit near genes that maintain the ends of chromosomes.
So "lung cancer genetics" is really several different genetics, depending on which lung cancer.
It does not estimate anyone's risk, and it is not used in any screening decision. Where lung cancer screening exists it is offered on age and smoking history — how much, for how long, how long ago — because those are the things that actually predict it and can be answered without a laboratory.
The useful actions are the ordinary ones: not starting, stopping if you have started, and taking a persistent cough, coughing blood, breathlessness or unexplained weight loss to a doctor rather than to a genome. Our smoking page covers the one place where genetics has something practical to say — which quitting medicine suits whom — and even there the finding is about a blood measurement rather than about this variant.
Positions joined since this page was written
What this is The text above discusses the variants this page was written around. Since then the catalogue has joined 58 more positions to it, by shared trait or shared paper. They are listed here by the paper each came from; the text does not describe them, and each variant page carries that study's own record.
Zhang Y et al. 2026, Nature communications rs951984 (near IREB2), rs11630236 (ADAMTS7), rs34638657 (HSD17B2-AS1), rs186184919 (TTC28), rs117371643 (PDS5B), rs3136673 (CCR3), rs37005 (LINC01511), rs12907065 (MORF4L1), rs376499689 (near PSMA4), rs1793150 (MPZL2), rs62329691 (near CLPTM1L), rs7243964 (GAREM1) and 12 more — PMID:42364979
Gabriel AAG et al. 2022, Journal of the National Cancer Institute rs11571815 (BRCA2), rs72905558 (near PTPRJ), rs3129813 (near UBQLN1P1), rs78062588 (ADAR), rs9258381 (HLA-F-AS1), rs6457312 (near HCG22), rs239933 (CEP43), rs3130302 (near NOTCH4) — PMID:35511172
Gorman BR et al. 2024, Nature communications rs11778371 (CHRNA2), rs7868253 (near MTAP), rs398278 (near RNASET2), rs239935 (near MIR3939), rs7300571 (near ADI1P3) — PMID:39366959
Zhu M et al. 2026, Genome medicine rs13167280 (TERT), rs12822733 (RAD52), rs3748522 (RAD52) — PMID:42152146
McKay JD et al. 2017, Nature genetics rs34662244 (ZSCAN12P1), rs67340775 (ZSCAN31), rs7383287 (HLA-DOB) — PMID:28604730
Sakaue S et al. 2021, Nature genetics rs7088860 (VTI1A), rs1794484 (near HLA-DQB1), rs78860372 (near MICC) — PMID:34594039
Wei X et al. 2024, International journal of cancer rs11196063 (VTI1A), rs11928222 (TP63), rs9275164 (near HLA-DQB1) — PMID:37846649
Verma A et al. 2024, Science (New York, N.Y.) rs201227858 (LPIN2), rs572975911 (PYCR1), rs186536803 (LINC01876) — PMID:39024449
Byun J et al. 2022, Nature genetics rs11607355 (JAML), rs2413932 (near COPS2) — PMID:35915169
Qin N et al. 2021, Frontiers of medicine rs2517873 (MCCD1P1) — PMID:32889700
Hu Z et al. 2011, Nature genetics rs753955 (MIPEP) — PMID:21725308
Dong M et al. 2025, Carcinogenesis rs147599930 (PLCL1) — PMID:40746155
Shen S et al. 2023, American journal of respiratory and critical care medicine rs140624366 (ATRN) — PMID:37167549
2026-06-27 · Zhang Y, et al. Nature Communications 2026, PMID:42364979
Development and validation of a multiancestry and multitrait polygenic risk score for lung cancer
Zhang Y, et al. (Nature Communications, 2026) is newly in the GWAS Catalog, with 87 associations across 1 trait ("Lung cancer"). The catalogue records its sample as 76,329 cases and 1,886,372 controls. 21 of the study's 87 positions are already on this site — 13 on the Lung Cancer page; 1 on the Prostate Cancer page; 1 on the Celiac Disease page — including rs951984 (near IREB2), rs37005 (LINC01511), rs12907065 (MORF4L1). This item was assembled by code from the catalogue's records; the paper is linked for the rest. PMID:42364979.
2026-08-08 · Prokunina-Olsson L, et al. Nature Communications 2026, PMID:42706231
Newly curated by the GWAS Catalog: 141 associations across 1 trait ("Bladder cancer"), from Prokunina-Olsson L, et al. in Nature Communications, 2026. Sample in the catalogue's record: 30,156 cases and 1,527,568 controls. Of its 70 positions, 33 already have pages here — 16 on the Bladder Cancer page; 1 on the Lung Cancer page; 1 on the Ulcerative Colitis page — including rs2294008 (PSCA), rs10094872 (MYC), rs2242652 (TERT). Put together by code from the catalogue's records; for anything more, follow the link to the paper. PMID:42706231.
2026-08-11 · Integrative Genome-Wide Association Study with eQTL Combined with Transcriptome Analysis Reveals SLC18A1 as a Novel Biomarker for Small Cell Lung Cancer. Current Medicinal Chemistry. 2026. DOI:10.2174/0109298673460777260725162800
This study combined three separate lines of evidence for small cell lung cancer (SCLC) risk genes: Mendelian randomization linking GWAS summary data (IEU Open GWAS Project) with expression quantitative trait loci from 31,684 people (eQTLGen), transcriptome data identifying genes differentially expressed in SCLC tissue, and immunohistochemistry on tumor samples to confirm protein-level expression. Four genes emerged where all three lines of evidence agreed: SLC18A1 (OR=1.72, 95% CI 1.07-2.78, P=0.025) was associated with increased SCLC risk and confirmed by tissue staining as more highly expressed in tumors from SCLC patients (58.6% of 29 patients) than controls (24.1%); CD93 (OR=0.66), TRPC6 (OR=0.35) and SLA (OR=0.58) were each associated with reduced risk and lower tumor expression. The confidence intervals are wide and the immunohistochemistry validation cohort is small (29 patients), so this should be read as a promising early candidate-biomarker signal rather than an established, widely replicated finding -- the authors themselves call for larger validation cohorts. This site's lung cancer page carries 44 variants; none of these four genes are currently among them, and the study reports Mendelian randomization gene-level evidence rather than a single lead rsID with a GWAS Catalog-style p-value, so this entry documents the finding at the condition level.
2025-07-01 · Genome-wide association study for lung cancer in 6531 African Americans reveals new susceptibility loci. Human Molecular Genetics. 2025. DOI:10.1093/hmg/ddaf059
Non-Hispanic African Americans have the highest lung cancer incidence (55.8 per 100,000) and death rate (37.2 per 100,000) of any US ethnic group, yet despite over 45 known susceptibility loci for lung cancer overall, few GWAS had focused specifically on this population. This study analyzed 2,267 African American lung cancer cases against 4,264 controls, finding 3 loci for overall lung cancer, 1 for adenocarcinoma and 4 for squamous cell carcinoma at genome-wide significance. Three were genuinely novel: near VWF (12p13.31) for overall lung cancer, and near GACAT3 (2p24.3) and LMAN1L (15q24.1) for squamous cell carcinoma specifically. The study also confirmed known risk loci with new or previously reported lead variants: CHRNA5 (15q25.1, already on this site's lung cancer page) and CYP2A6 (19q13.2) for overall lung cancer, and TRIP13 (5p15.33) and ERC1 (12p13.33) for squamous cell carcinoma. This directly addresses a documented health disparity with population-specific genetic evidence rather than extrapolating from European-derived risk loci. This site's lung cancer page carries 44 variants including CHRNA5; VWF, GACAT3, LMAN1L, CYP2A6, TRIP13 and ERC1 are new additions.
2025-11-22 · A two-stage genome-wide association study to identify novel genetic loci associated with irAEs in lung cancer patients receiving PD-1/PD-L1 inhibitors. Cancer Letters. 2025. DOI:10.1016/j.canlet.2025.218168
Three variants predict which lung cancer patients suffer severe side effects from immunotherapy
Immune checkpoint inhibitors (PD-1/PD-L1 inhibitors) have transformed lung cancer treatment, but immunotherapy-related adverse events (irAEs) -- the immune system attacking the patient's own healthy tissue as a side effect -- remain unpredictable and can be serious. No genetic predictor of irAEs had been definitively established before this study. Using a two-stage design (455 patients in discovery, 330 in independent validation, drawn from 1,467 total blood specimens collected), the study found three variants that validated in both stages: rs192921786 for pneumonitis (lung inflammation; discovery OR=9.57, validation OR=4.42), rs2498632 for anemia (discovery OR=0.50, protective; validation OR=0.65), and rs17080141 for thrombocytopenia (low platelets; discovery OR=3.16, validation OR=1.86). Patients carrying the risk allele at each locus were more likely to develop that specific side effect. This is a genuine pharmacogenomic safety signal -- distinct from cancer risk itself -- that could eventually help predict which patients need closer monitoring during immunotherapy, though the authors note further validation is warranted before clinical use. This site does not currently have a checkpoint-inhibitor drug page; this finding is recorded on the lung cancer condition page as a treatment-complication angle, distinct from the page's existing cancer-risk variants.
The 15q25 locus. Hung et al. genotyped 317,139 SNPs in 1,989 lung cancer cases and 2,625 controls across six central European countries, identifying 15q25 at P = 9 x 10-10, with replication in five further studies (2,513 cases, 4,752 controls) giving P = 5 x 10-20 overall and an estimated attributable risk of 14%. The association region contains CHRNA5, CHRNA3 and CHRNB4; the CHRNA5 non-synonymous variant D398N (rs16969968), which substitutes an amino acid at a conserved site in the second intracellular loop, is among the strongest markers, and rs8034191 is in the same haplotype block. Reported risks were statistically similar irrespective of smoking status or propensity to smoke.
Mechanism, unresolved. Thorgeirsson et al., publishing on the same cluster in the same month, reported effects on cigarettes per day and nicotine dependence together with risk of lung cancer and peripheral arterial disease, and interpreted the locus as acting through nicotine addiction. The competing interpretation rests on expression of these subunits in alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and on their binding of N'-nitrosonornicotine and related tobacco carcinogens — a plausible route to a direct pulmonary effect. Mediation analyses since have generally supported a substantial smoking-mediated component without excluding a residual direct effect; self-reported cigarettes per day is a coarse exposure measure, which limits how cleanly the two can be separated.
Current architecture. The 2017 OncoArray-based analysis (29,266 cases, 56,450 controls) identified 18 genome-wide significant loci, ten novel, with pronounced heterogeneity by histology: four associated with lung cancer overall and six with adenocarcinoma specifically. eQTL analysis in 1,425 normal lung tissue samples highlighted RNASET2, SECISBP2L and NRG1; other implicated loci include the cholinergic receptor CHRNA2 and telomere-maintenance genes. Effect sizes for individual common variants remain modest and no polygenic score is in clinical use for lung cancer.
Clinical position. Lung cancer screening with low-dose CT is offered on the basis of age and smoking history in the guidelines that recommend it; genotype has no role in eligibility, diagnosis or treatment selection, which is driven by histology and by somatic tumour testing (EGFR, ALK, ROS1, KRAS and others) — a different kind of genetics entirely, performed on the tumour rather than inherited.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Lung Cancer comes down to these specific, well-studied positions — not a diagnosis. 104 positions are linked to this page; the ones this page's own text discusses are shown first.
LRFN2 · rs2494938
See detailed info →SP4 · rs2285947
See detailed info →The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 47 of 104 linked studies with a resolved discovery ancestry.
Free to quote and reuse under CC BY 4.0. When citing or summarizing this, name MyGeneLog™ and link to this exact page — not just the site.
Lung Cancer. MyGeneLog™. https://www.mygenelog.com/conditions/lung-cancer
No. It is one common position associated with risk across large populations. The authors estimated the locus accounts for about 14% of cases at population level — that is an attributable fraction across everyone, not a probability for one person, and it cannot be turned into one.
That is the open question. The 2008 study reporting this variant found risks statistically similar irrespective of smoking status, and these receptor subunits are expressed in lung tissue and bind tobacco carcinogens. A second paper the same month found the cluster acting through how much people smoke. Both are large and real, and how much of the effect is smoking-mediated is still argued.
Two possible reasons, which is exactly the argument. It changes smoking behaviour, and smoking causes lung cancer. And the receptors themselves are present in lung cells and bind compounds in tobacco smoke, which would be a direct route. The evidence supports the first strongly and has never ruled out the second.
No. Screening, where it is offered, is decided on age and smoking history — the things that actually predict lung cancer and that need no laboratory. No guideline uses this or any other common variant for eligibility.
No, and the difference matters. Tumour testing looks for changes acquired by the cancer itself — EGFR, ALK, ROS1 and others — and those results choose treatments. This page is about inherited variation, which does not.
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