…Psychiatric genetics has largely moved away from historical candidate association studies, as most candidate genes failed to show associations in GWAS. In fact, a study that analyzed results from a schizophrenia GWAS showed that common variants in 25 historical candidate genes, including COMT, BDNF and DISC1, were no more associated with schizophrenia than control sets of non-candidate genes. Even for candidates that turned out to be associated with schizophrenia (eg. DRD2 and GRM3), their biological relevance remains unclear considering there are many other genes with a stronger association. Another study depicted a similar scenario for depression. However, despite the lack of success in candidate studies, a PubMed search for COMT revealed 269 research outputs published in 2020 alone (checked on January 20th, 2021). Many of these tested this gene for association with complex traits like pain, cognitive performance, behaviors, etc., even though the evidence of association between COMT and behavioral, psychiatric or neurological outcomes is weak, according to a phenome-wide association study (PheWAS) from the GWAS Atlas, which analyzed 4,756 GWAS results (Figure 1).
…considering the polygenic nature underlying complex human traits and the limitations of the candidate approach, we should be ditching association studies, especially if these are based solely on historical gene relevance. Psychiatrists, geneticists and neuroscientists must reconsider the cost-benefits of candidate studies when there is no prior robust evidence of trait association…