Previous work4 reported that depression defined through minimal phenotyping shows enrichment of h2SNP in regions of the genome encoding genes specifically and highly expressed in central nervous system (CNS) tissues represented in Genotype-Tissue Expression (GTEx)47 project. We assessed this in the definitions of depression in the UK Biobank using LDSC-SEG48. As shown in Fig. 5, neither strictly defined MDD (LifetimeMDD) nor MDD defined on the basis of structured clinical assessments in PGC1-MDD showed significant CNS enrichments, even though larger and more heterogeneous cohorts did (Methods, Supplementary Note, Supplementary Table 1 and Extended Data Fig. 4). Notably, the minimal phenotyping definition GPpsy showed a significant CNS enrichment, as did the no-MDD help-seeking definition GPNoDep, neuroticism, smoking, and other disorders in the PGC44, such as schizophrenia49 and bipolar disorder50. Our analysis shows that the degree of CNS enrichment does not relate to the strictness of the definition of MDD and is neither sufficient nor valid evidence that any particular definition of depression better represents MDD or captures the biological mechanisms behind MDD.
