Genetic stratification of depression by neuroticism: revisiting a diagnostic tradition

Background. Major depressive disorder and neuroticism 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 of depression (from the Psychiatric Genomics Consortium, 23andMe, and UK Biobank) and compared them to genome-wide association studies (GWAS) of neuroticism (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only neuroticism, 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 neuroticism.
Results. We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with neuroticism. The overlapping common genetic variance of depression and neuroticism was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that was not shared with neuroticism, was positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with neuroticism, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease, and age of first birth. Independent of depression, neuroticism 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 neuroticism, there are also non-neuroticism related features of depression that may be useful for further patient or phenotypic stratification.