A large-scale multi-ancestry genome-wide study accounting for smoking bahavior identifies multiple genome-wide significant loci for systolic and diastolic blood pressure

Genome- wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify novel BP loci and extend our knowledge of its genetic architecture. We performed genome -wide association meta -analys es of systolic and diastolic BP incorporating gene -smoking interactions in 610,091 individuals . Stage 1 analysis examined ~18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow -up analysis of promising variants in 480 ,178 additional individuals from fiv e ancestr ies . We identifie d 15 new loci that were genome- wide significant (P < 5 ×10 -8 ) in Stage 1 and formally replicated in Stage 2 . A combined Stage 1 and 2 meta -analysis identified 66 additional genome - wide significant loci ( 13, 35, and 18 loci in European, African and trans -ancestry, respectively ). A total of 5 6 k nown BP loci were also identified by our results (P < 5 ×10 -8 ). O f the newly identified loci , 10 sho wed significant interaction with smoking status , but none of them were replicated in Stage 2 . Several loci were identified in African ancestry , highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with c ardiometabolic and addiction traits . They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function ( CDKN1B , BCAR1 -CFDP1 , PXDN , EEA1 ), ciliopathies ( SDCCAG8, RPGRIP1L ), telomere maintenance ( TNKS , PINX1 , AKTIP ) , and cen tral dopaminergic signaling ( MSRA , EBF2 )