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

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

doi:10.1101/2025.10.06.25337440

Genetic & Genomic MedicinemedRxivOct 6, 2025

Preprint

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

Mengyu Zhang iD, Michael R. Brown iD, Amy R. Bentley iD, Thomas W. Winkler iD, Raymond Noordam iD, Pavithra Nagarajan iD, Bohong Guo iD, Songmi Lee iD, Karen Schwander iD, Wenyi Wang iD, Kenneth E. Westerman iD, Jeffrey R. O’Connell iD, Farah Ammous iD, Anna D. Argoty-Pantoja iD, Traci M. Bartz iD, Chiara Batini iD, Palwendé Romuald Boua iD, Heather Jane Cordell iD, Laia Díez-Ahijado iD, Latchezar M. Dimitrov iD, Anh N. Do iD, Jiawen Du iD, Mary Furlan Feitosa iD, Ayush Giri iD, Franco Giulianini, , Bertha Hidalgo iD

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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 x 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.