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Background: Depression is a debilitating mental disorder that often coexists with anxiety. The genetic mechanisms of depression and anxiety have considerable overlap, and studying depression in non-anxiety samples could help to discover novel gene. We assess the genetic variation of depression in non-anxiety samples, using genome-wide association studies (GWAS) and linkage disequilibrium score regression (LDSC)., Methods: The GWAS of depression score and self-reported depression were conducted using the UK Biobank samples, comprising 99,178 non-anxiety participants with anxiety score <5 and 86,503 non-anxiety participants without self-reported anxiety, respectively. Replication analysis was then performed using two large-scale GWAS summary data of depression from Psychiatric Genomics Consortium (PGC). LDSC was finally used to evaluate genetic correlations with 855 health-related traits based on the primary GWAS., Results: Two genome-wide significant loci for non-anxiety depression were identified: rs139702470 ( p  = 1.54 × 10 -8 , OR = 0.29) locate in PIEZO2 , and rs6046722 ( p  = 2.52 × 10 -8 , OR = 1.09) locate in CFAP61. These associated genes were replicated in two GWAS of depression from PGC, such as rs1040582 ( p replication GWAS1  = 0.02, p replication GWAS2  = 2.71 × 10 -3 ) in CFAP61 , and rs11661122 ( p replication GWAS1  = 8.16 × 10 -3 , p replication GWAS2  = 8.08 × 10 -3 ) in PIEZO2. LDSC identified 19 traits genetically associated with non-anxiety depression ( p  < 0.001), such as marital separation/divorce ( rg  = 0.45, SE = 0.15)., Conclusions: Our findings provide novel clues for understanding of the complex genetic architecture of depression.