Depressive disorders are among the leading causes of disability worldwide. Genome-wide association studies of common variants of depressive disorders have identified 178 risk loci, yet mechanisms remain elusive due to the very small effects of common variants. Certain rare variants may have larger effects, but exome and genome sequencing studies to date have been underpowered to detect effects of specific rare variants. One approach to address these limitations is to utilize population isolates, like the Old Order Amish (OOA), in which certain rare variants become enriched due to the population bottleneck effect. This study aimed to identify rare variants associated with depressive symptoms, utilizing whole exome sequencing (WES) and phenotypic data from two OOA cohorts (N = 5,052), the Amish Wellness Study and the Amish Connectome Project. We identified five significant SNP-depressive symptoms associations. Case-series phenotyping revealed high depressive symptoms screening scores across carriers of each variant compared to non-carriers.