Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain…, Howard et al, 2019

[cassava7]

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder.

To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression.

We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions.

In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction.

These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.

https://doi.org/10.1038/s41593-018-0326-7

Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522363/

 

[rvallee]

Not sure how accurate, but I saw a thread on Reddit today that said that rates of depression diagnosis in US children is around 25%. Which wouldn't be surprising given the lazy default of mindlessly slapping mental health labels of everyone. It seems about right on with claims of MUS, which are basically things medicine doesn't understand, and is probably a massive undercount.

And there's just no way any depression cohort is anything but a kludged up mix of people with various issues thrown together. Decades of putting garbage into all health records will do that.

Even if they are very large in size, those cohorts are not a single identity, probably have worse odds of being coherent than whatever makes up "chronic fatigue". It may as well be a MUS cohort, or a "failed by medicine" cohort, for all that it matters.

I'm pretty sure DecodeME will be far more homogeneous than this study, even given how difficult it will be.

 

[cassava7]

Heterogeneity is indeed likely to have been a limiting factor; for instance, the case definition in the UK Biobank cohort was broad:

Within UK Biobank we used the broad definition of depression [5] with more detailed phenotypic information available in that paper.

In summary, case and control status of broad depression was defined by the participants’ response to the questions ‘Have you ever seen a general practitioner for nerves, anxiety, tension or depression?’ or ‘Have you ever seen a psychiatrist for nerves, anxiety, tension or depression?’.

Exclusions were applied to participants who were identified with bipolar disorder, schizophrenia, or personality disorder using self-declared data following the approach of Smith, et al. [54] as well as prescriptions for antipsychotic medications.

This provided a total of 127,552 cases and 233,763 controls (n = 361,315, prevalence = 0.353) for analysis.

Nonetheless, it remains interesting that no serotonin-related genes were found to be involved; it would have been reasonable to expect a signal, even if just a small one.