Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depressive disorder

Abstract

Major depressive disorder (MDD) is a notably complex illness with a lifetime prevalence of 14%.1 It is often chronic or recurrent and is thus accompanied by considerable morbidity, excess mortality, substantial costs, and heightened risk of suicide.2-7 MDD is a major cause of disability worldwide. 8 We conducted a genome-wide association (GWA) meta-analysis in 130,664 MDD cases and 330,470 controls, and identified 44 independent loci that met criteria for statistical significance. We present extensive analyses of these results which provide new insights into the nature of MDD. The genetic findings were associated with clinical features of MDD, and implicated prefrontal and anterior cingulate cortex in the pathophysiology of MDD (regions exhibiting anatomical differences between MDD cases and controls). Genes that are targets of antidepressant medications were strongly enriched for MDD association signals (P=8.5x10 -10 ), suggesting the relevance of these findings for improved pharmacotherapy of MDD. Sets of genes involved in gene splicing and in creating isoforms were also enriched for smaller MDD GWA P-values, and these gene sets have also been implicated in schizophrenia and autism. Genetic risk for MDD was correlated with that for many adult and childhood onset psychiatric disorders. Our analyses suggested important relations of genetic risk for MDD with educational attainment, body mass, and schizophrenia: the genetic basis of lower educational attainment and higher body mass were putatively causal for MDD whereas MDD and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for MDD, and a continuous measure of risk underlies the observed clinical phenotype. MDD is not a distinct entity that neatly demarcates normalcy from pathology but rather a useful clinical construct associated with a range of adverse outcomes and the end result of a complex process of intertwined genetic and environmental effects. These findings help refine and define the fundamental basis of MDD.Twin studies attribute ~40% of the variation in liability to MDD to additive genetic effects (heritability, ℎ " ), 9 and ℎ " may be greater for recurrent, early-onset, and postpartum MDD. 10,11 GWA studies of MDD have had notable difficulties in identifying loci. 12 Previous findings suggest that an appropriately designed study should identify susceptibility loci. Direct estimates of the proportion of variance attributable to genome-wide SNPs (SNP heritability, ℎ #$% " ) indicate that around a quarter of the ℎ " for MDD is due to common genetic variants. 13,14 Although there were no significant findings in the initial Psychiatric Genomics Consortium (PGC) MDD mega-analysis (9,240 MDD cases) 15 or in the CHARGE meta-analysis of depressive symptoms (34,549 respondents), 16 more recent studies have proven modestly successful. A study of Han Chinese women (5,303 MDD cases) identified two genome-wide significant loci, 17 a meta-analysis of depressive symptoms (161,460 indi...

Genome-wide association study of depressive symptoms in the Hispanic Community Health Study/Study of Latinos

“…At the Bonferroni-corrected p-value threshold of .0006 (i.e., .05/80 tests), the GRS constructed from SNPs with p-values < 0.001 in the combined PGC MDD2 and 23andme cohorts (Wray et al, 2017) were significantly associated with all four depression phenotypes (Supplemental Table 17) - original depressive symptom score : β = 0.012, 95% CI=(0.006,0.017), p = .00004; adjusting for medication use : β = 0.013, 95% CI=(0.007,0.019), p = .00004; excluding medication users : β = 0.011, 95% CI=(0.005,0.017), p = .0001; binary depression: OR = 1.001, 95% CI=(1.000, 1.001), p = .0004. The p < 10 −4 GRS was also significantly associated with depression in the analysis excluding medication users ( p = .0004).…”

“…An r-value < .05 indicates that the SNP is associated in the same direction in both the discovery GWAS and HCHS/SOL GWAS. We studied the generalization of genetic associations from European ancestry populations to Hispanics/Latinos, using the three largest GWAS of depression to date (Direk et al, 2016; Okbay et al, 2016; Wray et al, 2017) as the discovery datasets.…”

“…Third, to evaluate the extent to which GWAS findings in European samples were, in aggregate, significantly associated with depressive symptoms in Hispanics/Latinos, we constructed unweighted genetic risk scores (GRS) (Moon et al, 2017; Qi et al, 2017) using summary statistics from three published GWAS of European populations (Direk et al, 2016; Wray et al, 2017; Okbay et al, 2016) and then evaluated the strength of association between these GRS in HCHS/SOL. Eight sets of GRS were developed using SNPs with p-value thresholds in the discovery GWAS of p T < .05, p T < .01, p T < .001, p T < 10 −4 , p T < 10 −5 , p T < 10 −6 , p T < 10 −7 , and p T < 10 −8 ; within each p-value threshold, SNPs were pruned to identify independent SNPs within a 500kb window.…”

The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods

“…This could have led to the different sets of cases having different genetic architectures. However, the experience of the PGC (and other groups) provides strong evidence that, if this is true, the adverse impact is small relative to the large benefits of an increased sample (7, 32). Finally, the SE and DK collections enable linkage with other national registers that can provide a comprehensive characterization of psychiatric and somatic comorbidity, whereas these auxiliary data are not available in the US and ANZ.…”

Twin Study of Early-Onset Major Depression Finds DNA Methylation Enrichment for Neurodevelopmental Genes

“…Twin and family studies robustly demonstrate that genetic factors play a role in risk for MD, with heritability estimates of roughly 35% for MD and 45% for early-onset MD 9 . The largest meta-analysis of molecular genetic studies of MD recently identified 44 independent loci, underscoring the centrality of genetic factors in the etiology of MD 10 . Twin study variance component analyses also indicate a considerable contribution of unique environmental risk factors to MD 11 .…”