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Background  Recent genome-wide association studies have uncovered genomic loci that underlie an increased risk for atrial fibrillation, the major cardiac arrhythmia in humans. The most significant locus is located in a gene desert at 4q25, approximately 170 kilobases upstream of  PITX2,  which codes for a transcription factor involved in embryonic left-right asymmetry and cardiac development. However, how this genomic region functionally and structurally relates to  PITX2  and atrial fibrillation is unknown.    Results  To characterise its function, we tested genomic fragments from 4q25 for transcriptional activity in a mouse atrial cardiomyocyte cell line and in transgenic mouse embryos, identifying a non-tissue-specific potentiator regulatory element. Chromosome conformation capture revealed that this region physically interacts with the promoter of the cardiac specific isoform of  Pitx2 . Surprisingly, this regulatory region also interacts with the promoter of the next neighbouring gene,  Enpep , which we show to be expressed in regions of the developing mouse heart essential for cardiac electrical activity.    Conclusions  Our data suggest that de-regulation of both  PITX2  and  ENPEP  could contribute to an increased risk of atrial fibrillation in carriers of disease-associated variants, and show the challenges that we face in the functional analysis of genome-wide disease associations.    Electronic supplementary material  The online version of this article (doi:10.1186/s12915-015-0138-0) contains supplementary material, which is available to authorized users.

Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP