Large-Scale Gene-Smoking Interactions and Fine Mapping Study Identifies Multiple Novel Blood Pressure Loci in over 1 Million Individuals

Q: What are the key findings of this study?

Gene-smoking interaction meta-analyses across 1,188,241 individuals identified 1,753 independent blood pressure loci, including 12 novel loci at genome-wide significance (P < 5 × 10^-9).

Q: What is the clinical evidence from this study?

Study design: Meta-Analysis. Population: Blood pressure regulation and hypertension (n=1188241). Intervention: Gene-smoking interactions (genetic variants interacting with current smoking status, cigarettes per day, and pack years) vs. Non-current cigarette smokers or marginal genetic effect models excluding smoking exposures. Primary outcome: Identification of genome-wide significant genetic loci associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) accounting for smoking interactions (p=<5×10^-9).

Q: What does this research mean for the field?

Accounting for gene-smoking interactions reveals twelve novel loci associated with blood pressure regulation at genome-wide significance across diverse populations. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To identify novel blood pressure loci and uncover underlying biological pathways by modeling interactions between genetic variants and cigarette smoking exposures across diverse populations.

Mengyu Zhang; Michael R. Brown; Amy R. Bentley; Thomas W. Winkler; Raymond Noordam; Pavithra Nagarajan; Bohong Guo; Songmi Lee; Karen Schwander; Wenyi Wang; Kenneth E. Westerman; Jeffrey R. O’Connell; Farah Ammous; Anna D. Argoty-Pantoja; Traci M. Bartz; Chiara Batini; Palwendé Romuald Boua; Heather Jane Cordell; Laia Díez-Ahijado; Latchezar M. Dimitrov; Anh N. Do; Jiawen Du; Mary Furlan Feitosa; Ayush Giri; Franco Giulianini; Valborg Guðmundsdóttir; Xiuqing Guo; Sarah E. Harris; Natalie R. Hasbani; Janina M. Herold; Keiko Hikino; Edith Hofer; Fang‐Chi Hsu; Anne Jackson; Minjung Kho; Aldi T. Kraja; Leo‐Pekka Lyytikäinen; Aline Meirhaeghe; Manon Muntaner; Masahiro Nakatochi; Giuseppe Giovanni Nardone; Teresa Nutile; Alessandro Pecori; Varun S. Rao; Rainer Rauramaa; Mihir M. Sanghvi; Aurora Santin; Botong Shen; Heather M. Stringham; Fumihiko Takeuchi; Ye An Tan; Jingxian Tang; Sébastien Thériault; Stella Trompet; Peter J. van der Most; Ya Xing Wang; Zhe Wang; Yujie Wang; Erin Bakshis Ware; Stefan Weiß; Ananda Rajitha Wickremasinghe; Chenglong Yu; Wanying Zhu; Md Abu Yusuf Ansari; Pramod Anugu; Bernhard Banas; R. Graham Barr; Til Bahadur Basnet; Eric Boerwinkle; Max Breyer; Ulrich Broeckel; Luke Bryant; Brian E. Cade; Silvia Camarda; William Checkley; Miao-Li Chee; Guanjie Chen; Kayesha Coley; Stacey D. Collins; Martin H. de Borst; Lisa de las Fuentes; Ian J. Deary; Christian Enzinger; Tariq O. Faquih; Jessica D. Faul; Lilian Fernandes Silva; Victoria Gauthier; Adam D. Gepner; Mathias Gorski; Hans Jörgen Grabe; Mariaelisa Graff; C. Charles Gu; Jiang He; Sami Heikkinen; Bertha Hidalgo

doi:10.1101/2025.10.06.25337440

October 7, 2025Open Access

Large-Scale Gene-Smoking Interactions and Fine Mapping Study Identifies Multiple Novel Blood Pressure Loci in over 1 Million Individuals

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Key result

Gene-smoking interaction meta-analysis identifies 12 novel blood pressure loci across ~1.2 million individuals.

P<5×10^-9
n=1,188,241

Why the study?

Cigarette smoking influences BP levels, and studying potential gene-smoking interactions can help discover novel loci and provide insights into biological pathways for smoking-associated BP regulation.

Does accounting for interactions between genetic variants and cigarette smoking exposures identify novel genetic loci and biological pathways regulating systolic blood pressure, diastolic blood pressure, and pulse pressure in a multi-ancestry population?

Key Points

To identify novel blood pressure loci and uncover underlying biological pathways by modeling interactions between genetic variants and cigarette smoking exposures across diverse populations.
Conducted a genome-wide association meta-analysis across 66 studies including 1,188,241 individuals from five ancestry groups: 804,275 European, 246,825 East Asian, 86,580 African, 37,949 Hispanic admixed, and 12,612 South Asian.
Evaluated systolic blood pressure, diastolic blood pressure, and pulse pressure using 1-degree-of-freedom interaction and 2-degree-of-freedom joint tests accounting for current smoking status, cigarettes per day, and pack years.
Prioritized candidate causal variants using SuSiEgxe, a two-degree-of-freedom fine-mapping method, combined with functional annotation, tissue-specific expression quantitative trait loci, and chromatin interaction data.
Identified 12 novel loci for blood pressure traits at genome-wide significance (P < 5 × 10^-9), including two for systolic blood pressure, six for diastolic blood pressure, and four for pulse pressure.
Revealed two novel loci in 1-degree-of-freedom interaction tests: rs35975869 for cigarettes-per-day interaction on pulse pressure (P_GxE = 4.1 × 10^-10) and rs61840542 for current-smoking interaction on systolic blood pressure (P_GxE = 4.7 × 10^-9).
Demonstrated that smoking status modified the genetic effects of six variants on blood pressure, such as rs3782886-T associating with higher pulse pressure in smokers (beta = 1.09, P = 6.9 × 10^-22) compared to non-smokers (beta = 0.27, P = 3.9 × 10^-8).

Study Design

Type

Meta-Analysis (n=1,188,241)

Multicenter

Yes

Structured PICO

Does accounting for interactions between genetic variants and cigarette smoking exposures identify novel genetic loci and biological pathways regulating systolic blood pressure, diastolic blood pressure, and pulse pressure in a multi-ancestry population?

P

Population

1,188,241 adults (>18 years) across 66 studies in five ancestry groups (68% European, 21% East Asian, 7% African, 3% Hispanic admixed, 1% South Asian) evaluated for gene-smoking interactions on blood pressure.

E

Exposure

Interaction between genome-wide genetic variants (SNPs) and three cigarette smoking exposures: current smoking status (CURSMK), cigarettes per day (CPD), and pack years (PY), evaluated via 1-degree-of-freedom (1df) interaction tests, 2-degree-of-freedom (2df) joint tests, and SuSiEgxe 2df fine-mapping.

C

Comparator

Non-current smokers (in smoking-stratified analyses) and marginal genetic effect models (Model 2) that did not account for smoking exposures.

O

Outcome

Resting/sitting systolic blood pressure (SBP, mmHg), diastolic blood pressure (DBP, mmHg), and pulse pressure (PP, mmHg), adjusted for anti-hypertensive medication use (+15 mmHg to SBP and +10 mmHg to DBP), evaluated for genome-wide significant loci (P < 5 × 10^-9 and FDR < 0.05).surrogate

Main Result

p-value: p=<5×10^-9

Incorporating gene-smoking interactions and multi-ancestry 2df fine-mapping into blood pressure GWAS uncovers 12 novel genetic loci and highlights mitochondrial, endothelial, tight junction, and immune pathways linking smoking to hypertension.

Limitations

Statistical power to detect genetic effects remains limited in ancestry groups with a smaller number of participants such as South Asians and Hispanic admixed populations.
Residual confounding may still exist despite controlling for potential confounders such as population stratification, particularly for complex traits influenced by both genetic and environmental factors.
The quality of fine mapping in meta-analysis highly depends on the quality of linkage disequilibrium (LD) in the reference panel used, and mismatched panels could lead to misleading results on causal variants.
Limited statistical power to detect genetic effects in ancestry groups with smaller sample sizes, such as South Asians and Hispanic admixed populations.
Potential residual confounding for complex traits influenced by both genetic and environmental factors.
Dependence of fine-mapping quality on the linkage disequilibrium (LD) reference panel matching the study population group.

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Answers are grounded in this paper and cite their sources.

Implication

Incorporating smoking interactions extends BP GWAS discovery with 12 novel loci; hypothesis-generating for mitochondrial and immune pathways, not yet for clinical use.

Abstract

Cigarette smoking influences blood pressure (BP) levels. Studying and accounting for potential gene-smoking interactions can help discover novel loci and provide insights into biological pathways for smoking-associated BP regulation. We conducted a genome-wide association meta-analysis involving 1,188,241 individuals from 66 studies in five ancestry groups, analyzing systolic BP, diastolic BP, and pulse pressure while considering interactions between genetic variants and three smoking exposures: smoking status, cigarettes per day, and pack years. These analyses identified twelve novel loci for BP at genome-wide significance ( P < 5 × 10 −9 ), and highlighted biological processes including tight junction integrity, mitochondrial health, vascular relaxation, and endothelial function. In smoking status-stratified analyses, smoking modifies the genetic effect of six variants on BP. To prioritize likely causal, we developed and applied SuSiEgxe, a fine-mapping method based on a two-degree-of-freedom joint test using gene-environment interaction summary statistics. Fine-mapped loci uncovered immune-related pathway for smoking-associated BP regulation.

Discussion

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Cite This Study

Zhang et al. (2025) conducted a meta-analysis in Blood pressure regulation and hypertension (n=1,188,241). Gene-smoking interactions (genetic variants interacting with current smoking status, cigarettes per day, and pack years) vs. Non-current cigarette smokers or marginal genetic effect models excluding smoking exposures was evaluated on Identification of genome-wide significant genetic loci associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) accounting for smoking interactions (p=<5×10^-9). Gene-smoking interaction meta-analyses across 1,188,241 individuals identified 1,753 independent blood pressure loci, including 12 novel loci at genome-wide significance (P < 5 × 10^-9).

synapsesocial.com/papers/6adfaaeab1e464b304503c17 https://doi.org/10.1101/2025.10.06.25337440

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Large-Scale Gene-Smoking Interactions and Fine Mapping Study Identifies Multiple Novel Blood Pressure Loci in over 1 Million Individuals

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Large-Scale Gene-Smoking Interactions and Fine Mapping Study Identifies Multiple Novel Blood Pressure Loci in over 1 Million Individuals

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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