Atrial fibrillation (AF) is the most common cardiac arrhythmia and carries a significant risk of stroke and heart failure.
The molecular etiologies of AF are poorly understood, leaving patients with limited therapeutic options. AF has been recognized
as an inherited disease in almost 30% of patient cases. However, few genetic loci have been identified and the mechanisms
linking genetic variants to AF susceptibility remain unclear. By sequencing 193 probands with lone AF, we identified a Q76E
variant within the coding sequence of the bone morphogenetic protein (BMP) antagonist gremlin-2 (GREM2) that increases its
inhibitory activity. Functional modeling in zebrafish revealed that, through regulation of BMP signaling, GREM2 is required
for cardiac laterality and atrial differentiation during embryonic development. GREM2 overactivity results in slower cardiac
contraction rates in zebrafish, and induction of previously identified AF candidate genes encoding connexin-40, sarcolipin
and atrial natriuretic peptide in differentiated mouse embryonic stem cells. By live heart imaging in zebrafish overexpressing
wild-type or variant GREM2, we found abnormal contraction velocity specifically in atrial cardiomyocytes. These results implicate,
for the first time, regulators of BMP signaling in human AF, providing mechanistic insights into the pathogenesis of the disease
and identifying potential new therapeutic targets.