Genome-wide association study of depression phenotypes in UK Biobank (n = 322,580) identifies the enrichment of variants in excitatory synaptic pathways

Howard, D. M.; Adams, M. J.; Shirali, M.; Clarke, T.-K.; Marioni, R. E.; Davies, G.; Coleman, J. R. I.; Alloza, C.; Shen, X.; Barbu, M. C.; Wigmore, E. M.; Hagenaars, S.; Lewis, C. M.; Smith, D. J.; Sullivan, P. F.; Haley, C. S.; Breen, G.; Deary, I. J.; McIntosh, A. M.

doi:10.1101/168732

bioRxiv · 10.1101/168732

Genome-wide association study of depression phenotypes in UK Biobank (n = 322,580) identifies the enrichment of variants in excitatory synaptic pathways

Howard, D. M.·Adams, M. J.·Shirali, M.·Clarke, T.-K.·Marioni, R. E.·Davies, G.·Coleman, J. R. I.·Alloza, C.·Shen, X.·Barbu, M. C.·Wigmore, E. M.·Hagenaars, S.·Lewis, C. M.·Smith, D. J.·Sullivan, P. F.·Haley, C. S.·Breen, G.·Deary, I. J.·McIntosh, A. M.

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Abstract

Depression is a polygenic trait that causes extensive periods of disability and increases the risk of suicide, a leading cause of death in young people. Previous genetic studies have identified a number of common risk variants which have increased in number in line with increasing sample sizes. We conducted a genome-wide association study (GWAS) in the largest single population-based cohort to date, UK Biobank. This allowed us to estimate the effects of {approx} 8 million genetic variants in 320,000 people for three depression phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. Each phenotype was found to be significantly genetically correlated with the results from a previous independent study of clinically defined MDD. We identified 14 independent loci that were significantly associated (P < 5 x 10-8) with broad depression, two independent variants for probable MDD, and one independent variant for ICD-coded MDD. Gene-based analysis of our GWAS results with MAGMA revealed 46 regions significantly associated (P < 2.77 x 10-6) with broad depression, two significant regions for probable MDD and one significant region for ICD-coded MDD. Gene region-based analysis of our GWAS results with MAGMA revealed 59 regions significantly associated (P < 6.02 x 10-6) with broad depression, of which 27 were also detected by gene-based analysis. Variants for broad depression were enriched in pathways for excitatory neurotransmission, mechanosensory behavior, postsynapse, neuron spine and dendrite. This study provides a number of novel genetic risk variants that can be leveraged to elucidate the mechanisms of MDD and low mood.

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Howard, D. M., Adams, M. J., Shirali, M., Clarke, T.-K., Marioni, R. E., Davies, G., Coleman, J. R. I., Alloza, C., Shen, X., Barbu, M. C., Wigmore, E. M., Hagenaars, S., Lewis, C. M., Smith, D. J., Sullivan, P. F., Haley, C. S., Breen, G., Deary, I. J., McIntosh, A. M.. 2017-07-27. Genome-wide association study of depression phenotypes in UK Biobank (n = 322,580) identifies the enrichment of variants in excitatory synaptic pathways. https://doi.org/10.1101/168732

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