Background: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.
Methods: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a . p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.
Results: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10-9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10-9).
Conclusions: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

Additional Metadata
Keywords CHARGE consortium, Depressive symptoms, FHIT gene, Genome-wide association study, Major depressive disorder, Psychiatric Genomics Consortium
Persistent URL dx.doi.org/10.1016/j.biopsych.2016.11.013, hdl.handle.net/1765/95448
Journal Biological Psychiatry
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/201413 - European Network for Genetic and Genomic Epidemiology (ENGAGE)
Citation
Direk, N, Williams, S, Smith, J.A, Ripke, S, Air, T. (Tracy), Amare, A.T, … Sullivan, P.F. (2016). An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype. Biological Psychiatry, (online first). doi:10.1016/j.biopsych.2016.11.013