Abstract Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups using 1 degree of freedom (1df) interaction and 2df joint tests. Primary multi-ancestry analyses in 62,969 individuals in stage 1 identified 3 novel loci that were replicated in an additional 59,296 individuals in stage 2, including rs7955964 ( FIGNL2/ANKRD33 ) showing significant 1df interactions with long sleep duration and rs73493041 ( SNORA26/C9orf170 ) and rs10406644 ( KCTD15/LSM14A ) showing significant 1df interactions with short sleep duration (P int &lt; 5×10 −8 ). Secondary ancestry-specific two-stage analyses and combined stage 1 and 2 analyses additionally identified 23 novel loci that need external replication, including 3 and 5 loci showing significant 1df interactions with long and short sleep duration, respectively (P int &lt; 5×10 −8 ). Multiple genes mapped to our 26 novel loci have known functions in sleep-wake regulation, nervous and cardiometabolic systems. We also identified new gene by long sleep interactions near five known BP loci (≤1Mb) including NME7, FAM208A, MKLN1, CEP164 , and RGL3/ELAVL3 (P int &lt; 5×10 −8 ). This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure