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Depression GWAS Based on Minimal Phenotyping May Lead to Skewed Results

NEW YORK – An international team of researchers has shown that genome-wide association studies (GWAS) of major depressive disorder (MDD) that are based on the increasingly popular method of minimal phenotyping could lead to biased views of the genetic architecture of MDD and could impede researchers' ability to identify pathways specific to the disease.

Minimal phenotyping uses a small number of self-reported symptoms to identify a disease case. The researchers compared the genetic architecture of depression as defined via minimal phenotyping to that of depression using full diagnostic criteria in the UK Biobank.

As they reported in a study published on Monday in Nature Genetics, they found that genetic architecture for the disease as defined by minimal phenotyping had a lower genotype-derived heritability that couldn't be explained by the inclusion of milder cases. Also, a higher proportion of the genome contributed to a shared genetic liability with other conditions than for strictly defined MDD. Further, they noted, GWAS based on minimal phenotyping definitions preferentially identified loci that were not specific to MDD, and although the method generated highly predictive polygenic risk scores, the predictive power could also be explained entirely by large sample sizes rather than by specificity for MDD.

"We find that MDD defined by minimal phenotyping has a large nonspecific component, and if GWAS loci from these definitions are chosen for follow-up molecular characterization, they may not be informative about biology specific to MDD," the authors wrote.

The researchers began by identifying five ways that MDD could be defined in the UK Biobank. First, there were self-reports of participants seeking medical attention for depression or related conditions. Second, participants were diagnosed with "symptom-based" MDD if, in addition to meeting help-seeking criteria, they reported experiencing one or more of the two cardinal features of depression. Third, a "self-report" definition of MDD was based on participants' self-reports of all past and current medical conditions to trained nurses. Fourth, an electronic medical record (EMR) definition was derived from the International Classification of Diseases, primary and secondary illness codes in electronic health records. Finally, a "CIDI-based" diagnosis of lifetime MDD was available from individuals who answered an online mental health follow-up questionnaire.

Their analyses found that depression defined by minimal phenotyping had lower SNP-based heritabilities than more strictly defined depression. Self-report and help-seeking definitions had heritabilities of 15 percent or less whereas strictly defined MDD had a SNP-based heritability of 26 percent. The researchers also compared SNP-based heritability estimates from previous studies of MDD with their own results and found that they fit into the trend they observed: the less strict the criteria used to diagnose MDD, the lower the SNP-based heritability.

The researchers then examined the roles of a number of additional factors and found that minimal phenotyping definitions showed no significant difference between high and low environmental exposure risk factors, and that they did not include milder cases of MDD, as previously hypothesized.

"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."

Indeed, the researchers found minimal phenotyping definitions of depression shared more genetic loci with other psychiatric conditions than strictly defined MDD did, and that GWAS of minimal phenotyping definitions of depression primarily enabled the discovery of pathways that were shared with other conditions.

"Our findings indicate the need for ways to integrate both strict and minimal phenotyping approaches to determine which loci to prioritize for follow-up functional analyses," the authors concluded. "They also indicate a need for means to assess symptoms for diagnosing MDD with specificity at scale, rather than reliance on minimal phenotyping."

The researchers suggested the use of fast and accurate diagnostic methods that use a limited number of questionnaire items. For example, they said, computerized adaptive diagnostic screening may be as effective for the diagnosis of MDD as face-to-face diagnostic interviews with clinicians. "If successful, these attempts may lead to a dramatic expansion in the ability to collect data appropriate for psychiatric genetics," they added.