Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways, 2018, Howard et al

[Andy]

Note: the UK Biobank is not the same as the UK ME/CFS Biobank.

Abstract

Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing sample sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD.

We identify 17 independent loci that are significantly associated (P < 5 × 10−8) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent sample, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.

Open access at https://www.nature.com/articles/s41467-018-03819-3

 

[Snow Leopard]

There have been a lot of genetic false positives, but a high quality GWAS provides some confidence in the results. Certainly worth funding much research targeting these loci and seeing how they lead to depression.

 

[Hutan]

The article that @Snowdrop posted here
https://www.s4me.info/threads/all-mental-disorders-are-brain-disorders-not.3627/
makes some comment about genetic studies in depression as well as some interesting comments about issues with other types of medical research into mental illnesses.

Genetic studies have also often revealed associations that are both weak and unspecific. After a decade of GWAS null-findings for depression16, recent papers have identified a few SNPs that sometimes replicated across one or two datasets. But the explained variance is so low that it is usually not even mentioned in GWAS papers on depression17.

It is also relevant here to keep in mind that GWAS studies do usually not partial out important covariates … so if a study does explain 2% or 5% on Major Depression, one explanation is that it explains variance of correlated phenotypes18.

I haven't read all of the Howard et al paper. But they seemed to find more correlated genes in broad depression, which seems to be a heterogeneous diagnosis, rather than MDD which seems more likely to be a discrete illness, suggesting that there should be a lower level of confidence that finding these genes will help understand underlying processes.