Abstract
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. 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. 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. 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.
Highlights
Major depressive disorder (MDD) is a leading cause of morbidity worldwide, currently affecting approximately 4% of the world’s population (World Health Organization, 2017)
The pairwise genome-wide association studies (GWAS) analysis using depression results from the Psychiatric Genomics Consortium (PGC) and 23andMe and Neu results from UK Biobank revealed nine genomic regions that were significantly associated with depression but not with Neu
Several of the associated regions contained genes of known function: rs10913112 is downstream of RFWD2, a gene that can promote tumour growth (Dornan et al, 2004); rs4660091 is near the fumarate hydratase gene (FH) which is involved in the Krebs cycle; rs4143229 is in an intron of the ecto-NOX disulphide-thiol exchanger 1 gene (ENOX1) which is expressed in the nervous systems and has been implicated in autoimmune disorders (Landouré et al, 2012) and rs1343605 is near OLFM4, a gene that has been linked to depression (Wray et al, 2018), inflammation and cancer (Liu and Rodgers, 2016)
Summary
Major depressive disorder (MDD) is a leading cause of morbidity worldwide, currently affecting approximately 4% of the world’s population (World Health Organization, 2017). MDD is classified by the World Health Organisation and American Psychiatric Association according to its severity, its recurrence or chronicity, and the presence or absence of psychotic symptoms. This approach aims to maximise the reliability of MDD’s diagnosis while being agnostic about its underlying aetiology until robust evidence of causal mechanisms can be used to stratify the condition. Major depressive disorder and neuroticism (Neu) share a large genetic basis. 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. While genetic risk factors for depression are largely shared with Neu, there are non-Neu-related features of depression that may be useful for further patient or phenotypic stratification
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