DNA methylation of the <italic>BRD2</italic> promoter is associated with juvenile myoclonic epilepsy in Caucasians.

Summary: Objective: Juvenile myoclonic epilepsy (JME) is a common adolescent‐onset genetic generalized epilepsy (GGE) syndrome. Multiple linkage and association studies have found that <italic>BRD2</italic> influences the expression of JME. The <italic>BRD2‐</italic>JME connection is further corroborated by our murine model; <italic>Brd2</italic> haploinsufficiency produces characteristics that typify the clinical hallmarks of JME. Neither we, nor several large‐scale studies of JME, found JME‐related <italic>BRD2</italic> coding mutations. Therefore, we investigated noncoding <italic>BRD2</italic> regions, seeking the origin of <italic>BRD2</italic>'s JME influence. <italic>BRD2's</italic> promoter harbors a JME‐associated single nucleotide polymorphism (rs3918149) and a CpG (C‐phosphate‐G dinucleotides) island (CpG76), making it a potential “hotspot” for JME‐associated epigenetic variants. Methylating promoter CpG sites causes gene silencing, often resulting in reduced gene expression. We tested for differences in DNA methylation at CpG76 in 3 different subgroups: (1) JME patients versus their unaffected family members, (2) JME versus patients with other forms of GGE, and (3) Caucasian versus non‐Caucasian JME patients. Methods: We used DNA pyrosequencing to analyze the methylation status of 10 <italic>BRD2</italic> promoter CpG sites in lymphoblastoid cells from JME patients of Caucasian and non‐Caucasian origin, unaffected family members, and also non‐JME GGE patients. We also measured global methylation levels and DNA methyl transferase 1 (DNMT1) transcript expression in JME families by standard methods. Results: CpG76 is highly methylated in JME patients compared to unaffected family members. In families with non‐JME GGE, we found no relationship between promoter methylation and epilepsy. In non‐Caucasian JME families, promoter methylation was mostly not associated with epilepsy. This makes the <italic>BRD2</italic> promoter a JME‐specific, ethnicity‐specific, differentially methylated region. Global methylation was constant across groups. Significance: <italic>BRD2</italic> promoter methylation in JME, and the lack of methylation in unaffected relatives, in non‐JME GGE patients, and in non‐Caucasian JME, demonstrate that methylation specificity is a possible seizure susceptibility motif in JME risk and suggests JME therapeutics targeting <italic>BRD2</italic>. [ABSTRACT FROM AUTHOR]