Implications for future research

The discovery of novel loci is commonly heralded as a major discovery. However, the discovery of genetic loci is only useful if they can be mapped to biological processes that advance our understanding of either disease etiology, disease progression, or targets for treatment. Therefore one should always make extra effort to link the loci discovered to known biological pathways as an additional quality check to avoid that spurious correlations affect the conclusions. In the works under discussion here, the SNPs discovered in the GWAS were mapped using FUMA¹ to genes. In further analyses, these genes were mapped to biological processes using a variety of tools. Due to the abstract nature of the phenotpe and the complex interactions of the brain functional connectome with mental health, we felt these quality checks were necessary to ensure the findings were robust. As of now, standards for validating findings in psychiatric genetics are largely lacking and therefore a more detailed guidelines should be formalized to streamline quality checks across studies.

Study on high-level, globalized metrics cannot and should not be the end stage of research with complex and distributed effects. Eventually, the results from these abstract measures should once again focus on specific targets that can be replicated in an in vitro setting. As previous research has shown severe reliability issues with for example candidate gene studes that proved to suffer from poor statistical power and insufficient grounding in direct biological processes², these pitfalls must be avoided using these GWAS approaches as well. Resources should always be allocated to ensure that the findings meet conservative statistical standards and that those findings that pass the statistical standards should be grounded in biology.

1.

Watanabe K, Taskesen E, van Bochoven A, Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nature Communications [Internet]. 2017 Nov 28;8(1):1826. Available from: https://doi.org/10.1038/s41467-017-01261-5

2.

Border R, Johnson EC, Evans LM, Smolen A, Berley N, Sullivan PF, et al. No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples. Am J Psychiatry. 2019 May 1;176(5):376–87.