Large-Scale Gene-Smoking Interactions and Fine Mapping Study Identifies Multiple Novel Blood Pressure Loci in over 1 Million Individuals
Zhang, M.; Brown, M. R.; Bentley, A. R.; Winkler, T. W.; Noordam, R.; Nagarajan, P.; Guo, B.; Lee, S.; Schwander, K.; Wang, W.; Westerman, K.; O'Connell, J. R.; Ammous, F.; Argoty-Pantoja, A. D.; Bartz, T. M.; Batini, C.; Boua, P. R.; Cordell, H. J.; Diez-Ahijado, L.; Dimitrov, L.; Do, A. N.; Du, J.; Feitosa, M. F.; Giri, A.; Giulianini, F.; Gudmundsdottir, V.; Guo, X.; Harris, S. E.; Hasbani, N. R.; Herold, J. M.; Hikino, K.; Hofer, E.; Hsu, F.-C.; Jackson, A. U.; Kho, M.; Kraja, A. T.; Lyytikäinen, L.-P.; Meirhaeghe, A.; Muntaner, M.; Nakatochi, M.; Nardone, G. G.; Nutile, T.; Palmer, N. D.
Show 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.
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