Abstract: Behçet's disease (BD) is a complex disease with genetic and environmental risk factors implicated in its etiology; however, its pathophysiology is poorly understood. To decipher BD's genetic underpinnings, we combined gene expression profiling with pathway analysis and association studies. We compared the gene expression profiles in peripheral blood mononuclear cells (PBMCs) of 15 patients and 14 matched controls using Affymetrix microarrays and found that the neuregulin signaling pathway was over-represented among the differentially expressed genes. The Epiregulin (EREG), Amphiregulin (AREG), and Neuregulin-1 (NRG1) genes of this pathway stand out as they are also among the top differentially expressed genes. Twelve haplotype tagging SNPs at the EREG-AREG locus and 15 SNPs in NRG1 found associated in at least one published BD genome-wide association study were tested for association with BD in a dataset of 976 Iranian patients and 839 controls. We found a novel association with BD for the rs6845297 SNP located downstream of EREG, and replicated three associations at NRG1 (rs4489285, rs383632, and rs1462891). Multifactor dimensionality reduction analysis indicated the existence of epistatic interactions between EREG and NRG1 variants. EREG-AREG and NRG1, which are members of the epidermal growth factor (EGF) family, seem to modulate BD susceptibility through main effects and gene–gene interactions. These association findings support a role for the EGF/ErbB signaling pathway in Electronic supplementary material The online version of this article (doi:10.1007/s00109-013-1022-4) contains supplementary material, which is available to authorized users. J. M. Xavier : T. Krug : B. V. Fonseca : S. A. Oliveira (*) Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal e-mail: aaoliveira@fm.ul.pt J. M. Xavier : T. Krug : B. V. Fonseca : S. A. Oliveira Instituto Gulbenkian de Ciência, Oeiras, Portugal F. Davatchi : F. Shahram : B. S. Abdollahi : A. Nadji : N. M. Shafiee : F. Ghaderibarmi Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran G. Jesus Hospital Infante D. Pedro, Aveiro, Portugal F. Barcelos : J. Vaz Patto Instituto Português de Reumatologia, Lisboa, Portugal J. Vedes Hospital de Sousa Martins, Guarda, Portugal M. Salgado Hospital Pediátrico de Coimbra, Coimbra, Portugal M. F. Moraes-Fontes Hospital Curry Cabral, Lisboa, Portugal J. Crespo Hospitais da Universidade de Coimbra, Coimbra, Portugal,BD pathogenesis that warrants further investigation and highlight the importance of combining genetic and genomic approaches to dissect the genetic architecture of complex diseases. Keywords Genetics . Microarray . Association study . Behçet's disease . Genetic epidemiology