Fetuses exposed to maternal anti-Ro60 autoantibodies can develop life threatening cardiac conduction disease and cardiomyopathy, manifestations of neonatal lupus. Recent data support a pathologic mechanism where immune complexes comprised of anti-Ro60 autoantibodies, Ro60 autoantigen and its associated non-coding RNA, engage Toll-like receptors (TLR) 7/8 and promote secretion of inflammatory and fibrotic mediators by macrophages. While maternal autoantibodies are necessary for this process, they are not sufficient and it is likely that fetal and environmental factors are required for full expression of disease. The goal of this study was to identify risk genes associated with neonatal lupus and TLR-dependent fibrosis. Candidate genes were identified by comparing genetic variation in 116 children with cardiac neonatal lupus to 3,351 controls. Ingenuity Pathway Analysis was used to generate a list of genes with fibrotic functions that showed a significant enrichment of associations with neonatal lupus (P=2.27x10-9). The contribution of in utero environmental factors to neonatal lupus was assessed using gene arrays from primary human macrophages stimulated with Ro60 immune complexes, an in vitro model of autoantibody-mediated injury. Macrophages stimulated with immune complexes up-regulated 891 genes of which, expression was reduced by at least 50% in the presence of TLR7/8 inhibitor. Comparison of neonatal lupus associated fibrosis genes and TLR7/8-dependent transcripts revealed 20 shared genes, which were ranked according to the P-value of the variant and ratio of transcript copy number for immune complex stimulated macrophages in the presence or absence of TLR7/8 inhibitor. Among the top candidate risk genes were: Relaxin receptor 1 (RXFP1), a G-protein coupled receptor that binds relaxin and has a role in collagen and connective tissue remodelling; inflammatory mediators C5 and TNF (previously reported to have genetic variation and functional role in neonatal lupus) and chemokine CXCL12. These data support the applicability of a novel model in which causal alleles may be identified by combining expression and association datasets to delineate the molecular mechanisms by which autoantibodies mediate injury.