Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

Abstract

Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.

Figure 1

(A) Manhattan plot of the observed –log₁₀ P-values of each variant for an association with depression in the meta-analysis (n = 807,553; 246,363 cases and 561,190 controls). Variants are positioned according to the GRCh37 assembly

Figure 2

(A) Significance of cell type enrichment using a partitioned heritability approach. The dashed line represents statistical significance after Bonferroni correction (-log₁₀P = 2.36) and * indicates significant enrichment for that cell type (B) Significance of enrichment estimates, based on genetic summary statistics, for brain regions using GTEx. The dashed line represents the Bonferroni cut-off for statistical significance (-log₁₀P = 2.41) and * indicates significant enrichment for that brain region (C) Significant enrichment P-values, based on genetic summary statistics, for brain cell regions using GTEx overlaid on a physical representation of brain anatomy The pseudo-coloring used in Figure 2C highlights the P-values of the regions of the brain in red that were significantly enriched (P < 0.05) for depression variants

Figure 3

Chord diagram of genes significantly associated (P < 2.80 × 10^-6) with depression and the second level Anatomical Therapeutic Chemical classifications to which interacting drugs have been assigned. The width of each line is determined by the number of drugs known to interact with each gene. The genes are ordered by significance with depression with those most significantly associated located at the top of the diagram The second level Anatomical Therapeutic Chemical classifications identified were: Stomatological preparations (A01), Drugs for acid related disorders (A02), Drugs for functional gastrointestinal disorders (A03), Bile and liver therapy (A05), Drugs for constipation (A06), Drugs used in diabetes (A10), Vitamins (A11), Mineral Supplements (A12), Anabolic agents for systemic use (A14), Blood substitutes and perfusion solutions (B05), Other hematological agents (B06), Cardiac therapy (C01), Diuretics (C03), Peripheral vasodilators (C04), Vasoprotectives (C05), Beta blocking agents (C07), Calcium channel blockers (C08), Corticosteroids, dermatological preparations (D07), Anti-acne preparations (D10), Other dermatological preparations (D11), Other gynecologicals (G02), Sex hormones and modulators of the genital system (G03), Urologicals (G04), Pituitary and hypothalamic hormones and analogues (H01), Corticosteroids for systemic use (H02), Antibacterials for systemic use (J01), Antivirals for systemic use (J05), Vaccines (J07), Antineoplastic agents (L01), Endocrine therapy (L02), Immunostimulants (L03), Immunosuppressants (L04), Anti-inflammatory and antirheumatic products (M01), Muscle relaxants (M03), Antigout preparations (M04), Drugs for treatment of bone diseases (M05), Anesthetics (N01), Analgesics (N02), Antiepileptics (N03), Anti-Parkinson drugs (N04), Psycholeptics (N05), Psychoanaleptics (N06), Other nervous system drugs (N07), Antiprotozoals (P01), Ectoparasiticides, incl. scabicides, insecticides and repellents (P03), Nasal preparations (R01), Drugs for obstructive airway diseases (R03), Antihistamines for systemic use (R06), Ophthalmologicals (S01), Otologicals (S02), Ophthalmological and otological preparations (S03), All other therapeutic products (V03), Diagnostic agents (V04), and Diagnostic radiopharmaceuticals (V09)