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Genetic stratification of depression by neuroticism: revisiting a diagnostic tradition

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  • Mark J Adams, Royal Edinburgh Hospital
  • ,
  • David M Howard, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK., Royal Edinburgh Hospital
  • ,
  • Michelle Luciano, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
  • ,
  • Toni-Kim Clarke, Royal Edinburgh Hospital
  • ,
  • Gail Davies, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
  • ,
  • W David Hill, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
  • ,
  • Daniel Smith, General Practice and Primary Care, Institute of Health and Wellbeing, University of Glasgow, Glasgow, Scotland.
  • ,
  • Ian J Deary, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
  • ,
  • David J Porteous, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland.
  • ,
  • Andrew M McIntosh, Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh, UK., Royal Edinburgh Hospital
  • ,
  • 23andMe Research Team
  • ,
  • Major Depressive Disorder Working Group of the Psychiatric Genomic Consortium

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.

Original languageEnglish
JournalPsychological Medicine
Volume50
Issue15
Pages (from-to)2526–2535
Number of pages10
ISSN0033-2917
DOIs
Publication statusPublished - Nov 2020

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