Meta-analysis argues for a female-specific role of MAOA-uVNTR in panic disorder in four European populations

Panic disorder (PD) is a common mental disorder, ranking highest among the anxiety disorders in terms of disease burden. The pathogenesis of PD is multifactorial with significant heritability, however only a few convincing risk genes have been reported thus far. One of the most promising candidates is the gene encoding monoamine oxidase A (MAOA), due to its key role in monoaminergic neurotransmission, established validity of animal models, and the efficacy of MAO inhibitors in the treatment of PD. A promoter repeat polymorphism in MAOA (MAOA‐uVNTR) impacts on gene expression; high‐expression alleles have been reported to increase the risk for PD. To further scrutinize the role of this polymorphism, we performed a formal meta‐analysis on MAOA‐uVNTR and PD using original data from four published European (Estonian, German, Italian, and Polish) samples and genotypes from three hitherto unpublished German PD samples, resulting in the largest (n = 1,115 patients and n = 1,260 controls) genetic study on PD reported to date. In the unpublished samples, evidence for association of MAOA‐uVNTR with PD was obtained in one of the three samples. Results of the meta‐analysis revealed a significant and female‐specific association when calculating an allelic model (OR = 1.23, P = 0.006). This sex‐specific effect might be explained by a gene‐dose effect causing higher MAOA expression in females. Taken together, our meta‐analysis therefore argues that high‐expression MAOA‐uVNTR alleles significantly increase the risk towards PD in women. However, epigenetic mechanisms might obfuscate the genetic association, calling for ascertainment in larger samples as well as assessment of the MAOA promoter methylation status therein. © 2012 Wiley Periodicals, Inc.