AbstractThe etiology of mood disorders remains elusive, despite our increasing understanding of the neurotransmitter systems and brain regions that are involved. We performed a large family‐based association study to test if the human kainate receptor GluR7 gene (GRIK3) is associated with bipolar disorder (BP) or recurrent major depressive disorder (R‐MDD). One hundred fifty‐three multiplex BP families from the National Institute of Mental Health (NIMH) Genetics Initiative on Bipolar Disorder were analyzed with the transmission disequilibrium test (TDT). We detected a significant linkage disequilibrium (LD) indicated by preferential maternal transmission of the GluR7 S310 allele to R‐MDD patients (P = 0.012), but not to bipolar I disorder (BPI) patients (P = 1.00). We performed a second independent study by applying the TDT in 81 parent–offspring triads from families that inherit recurrent early‐onset major depressive disorder (RE‐MDD). The results from this second study showed only a suggestive maternal association (P = 0.068). Our findings imply that the GluR7 gene is a susceptibility factor in R‐MDD and that the glutamatergic receptor system plays a critical role in the disease etiology. © 2006 Wiley‐Liss, Inc.