PT - JOURNAL ARTICLE AU - Na Cai AU - Joana A. Revez AU - Mark J Adams AU - Till F. M. Andlauer AU - Gerome Breen AU - Edna M. Byrne AU - Toni-Kim Clarke AU - Andreas J. Forstner AU - Hans J. Grabe AU - Steven P. Hamilton AU - Douglas F. Levinson AU - Cathryn M. Lewis AU - Glyn Lewis AU - Nicholas G. Martin AU - Yuri Milaneschi AU - Ole Mors AU - Bertram Müller-Myhsok AU - Brenda W. J. H. Pennix AU - Roy H. Perlis AU - Giorgio Pistis AU - James B. Potash AU - Martin Preisig AU - Jianxin Shi AU - Jordan W. Smoller AU - Fabien Streit AU - Henning Tiemeier AU - Rudolf Uher AU - Sandra Van der Auwera AU - Alexander Viktorin AU - Myrna M. Weissman AU - MDD Working Group of the Psychiatric Genomics Consortium AU - Kenneth S. Kendler AU - Jonathan Flint TI - Minimal phenotyping yields GWAS hits of low specificity for major depression AID - 10.1101/440735 DP - 2019 Jan 01 TA - bioRxiv PG - 440735 4099 - http://biorxiv.org/content/early/2019/07/02/440735.short 4100 - http://biorxiv.org/content/early/2019/07/02/440735.full AB - Minimal phenotyping refers to the reliance on self-reported responses to one or two questions for disease case identification. This strategy has been applied to genome-wide association studies (GWAS) of major depressive disorder (MDD). Here we report that the genotype derived heritability (h2SNP) of depression defined by minimal phenotyping (14%, SE = 0.8%) is lower than strictly defined MDD (26%, SE = 2.2%), and that it shares as much genetic liability with strictly defined MDD (0.81, SE = 0.03) as it does with neuroticism (0.84, SE = 0.05), a trait not defined by the cardinal symptoms of depression. While they both show similar shared genetic liability with the personality trait neuroticism, a greater proportion of the genome contribute to the minimal phenotyping definitions of depression (80.2%, SE = 0.6%) than to strictly defined MDD (65.8%, SE = 0.6%). We find that GWAS loci identified in minimal phenotyping definitions of depression are not specific to MDD: they also predispose to other psychiatric conditions. Finally, genetic predictors based on minimal phenotyping definitions are not predictive of strictly defined MDD in independent cohorts. Our results reveal that genetic analysis of minimal phenotyping definitions of depression identifies non-specific genetic factors shared between MDD and other psychiatric conditions. Reliance on results from minimal phenotyping for MDD may thus bias views of the genetic architecture of MDD and impedes ability to identify pathways specific to MDD.