GWAS may create roadblock in MDD discovery

Popular minimal phenotyping method could inhibit identification of pathways specific to depression

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Genome-wide association study (GWAS) efforts have been a boon to drug discovery and development efforts, but an international team of researchers recently found that minimal phenotyping may pose problems to efforts in finding treatable pathways for major depressive disorder (MDD).
Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, a method that is increasingly used in GWAS-based research.
As the researchers note in the paper “Minimal phenotyping yields genome-wide association signals of low specificity for major depression,” published recently in Nature Genetics, there are differences in genetic architecture between depression that is defined by minimal phenotyping and strictly defined MDD. In the case of the minimal phenotyping-defined depression, they say that the group “has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD.”
Thus, they report that GWAS based on minimal phenotyping definitions “preferentially identifies loci that are not specific to MDD.” The method generates highly predictive polygenic risk scores, but they say that the predictive power can be explained “entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.”
The researchers began by identifying five ways that MDD could be defined in the UK Biobank, and one of the things they discovered was that self-reported and help-seeking definitions had single-nucleotide polymorphism (SNP)-based heritabilities of 15 percent or lower; on the other hand, strictly defined MDD had a SNP-based heritability of around 26 percent. The team then went on to examine the roles of a number of additional factors and found that minimal phenotyping definitions showed no significant difference between environmental exposure risk factors and that did not include milder cases of MDD.
“Inclusion of milder cases is equivalent to lowering the threshold for disease liability in the population above which cases for MDD are defined,” the authors wrote. “Under the liability threshold model, this did not reduce the [SNP-based heritability]. Instead, we showed through simulations that the lower [SNP-based heritability] of minimal phenotyping definitions of depression may be due to misdiagnosis of controls as cases of MDD and misclassification of those with other conditions as cases of MDD.”
One of the team’s conclusions, therefore, was that there is a need to integrate both strict and minimal phenotyping approaches “to determine which loci to prioritize for follow-up functional analyses ... [there is also] a need for means to assess symptoms for diagnosing MDD with specificity at scale, rather than reliance on minimal phenotyping.”

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