Genetic stratification of depression by neuroticism: revisiting a diagnostic tradition

Abstract

Background: Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression.

Methods: We analysed summary statistics from genome-wide association studies (GWAS) of depression (from the Psychiatric Genomics Consortium, 23andMe and UK Biobank) and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu.

Results: We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education.

Conclusion: Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification.

Keywords: Diagnosis; genetic correlation; genome-wide association study; major depressive disorder; neuroticism.

Fig. 1.

Manhattan plot of pairwise GWAS of depression and Neu with genomic segments partition by association with depression-only (blue), Neu only (orange), both traits (green), separate associations (red) or neither trait (grey).

Fig. 2.

Genetic correlations of traits with MD and with Neu. Full, unadjusted correlations (green circles) and partial genetic correlations after adjusting for the other variable (purple triangles) with 95% confidence intervals. We grouped traits based on the patterning of full and partial genetic correlations: both = genetically correlated with MD and Neu, with specific or entirely shared overlap; MD specific = genetically correlated with depression but not Neu; MD·adjNeu specific = fully correlated with both MD and Neu, but partially correlated with only MD; Possible MD·adjNeu specific = fully or partially correlated with depression and not Neu, but substantial overlap in effect sizes; Neu·adjMD specific: fully correlated with both MD and Neu, but partially correlated with only Neu; Neu specific = genetically correlated with Neu but not depression; neither = not genetically correlated with either depression or Neu.