An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

Biol Psychiatry. 2017 Sep 1;82(5):322-329. doi: 10.1016/j.biopsych.2016.11.013. Epub 2016 Dec 8.

Abstract

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.

Keywords: CHARGE consortium; Depressive symptoms; FHIT gene; Genome-wide association study; Major depressive disorder; Psychiatric Genomics Consortium.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Anhydride Hydrolases / genetics
  • Depression / genetics*
  • Depressive Disorder / genetics*
  • European Continental Ancestry Group / genetics
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Neoplasm Proteins / genetics
  • Phenotype

Substances

  • Neoplasm Proteins
  • fragile histidine triad protein
  • Acid Anhydride Hydrolases