PT - JOURNAL ARTICLE AU - Na Cai AU - Kenneth S. Kendler AU - Jonathan Flint TI - Minimal phenotyping yields GWAS hits of low specificity for major depression AID - 10.1101/440735 DP - 2018 Jan 01 TA - bioRxiv PG - 440735 4099 - http://biorxiv.org/content/early/2018/10/11/440735.short 4100 - http://biorxiv.org/content/early/2018/10/11/440735.full AB - Background Minimal phenotyping refers to the reliance on self-reported responses to one or two questions for disease case identification instead of full diagnostic criteria. This strategy has been applied in genome-wide association studies (GWAS) on major depressive disorder (MDD), leading to lowering of phenotyping costs, increasing sample sizes, and more GWAS hits. It assumes that any increase in diagnostic noise, and its impact on the nature of GWAS loci thus identified, can be mitigated by the large increase in sample size.Methods We assess the impact of using different definitions of MDD in 337,198 White-British, unrelated samples in the UKBiobank with GWAS, analyses of heritability and genetic correlation, and comparison with previously published statistics on MDD and other psychiatric conditions. Definitions of MDD include seeking medical help for anxiety or depression, reporting MDD or its cardinal symptoms, and meeting full DSM criteria for MDD.Findings Heritability of depression defined by minimal phenotyping (<15%) is lower than DSM-based MDD (26%), and the former shares as much genetic liability with DSM-MDD (0·81) as it does a non-MDD help-seeking condition (0·84). While minimal phenotyping-based depression and DSM-based MDD show similar shared genetic liability with other conditions like neuroticism, a greater proportion of the genome contribute to the former (77%) than the latter (64%). Enrichment of heritability in CNS specific genes is found in both minimal phenotyping definitions of depression and other psychiatric conditions, but not DSM-MDD. GWAS loci identified in the minimal phenotyping definitions of depression, even when found in DSM-based MDD, show similar effects in other psychiatric conditions.Interpretation Using minimal phenotyping strategy for GWAS, when applied to MDD, carries significant potential risks. It primarily identifies non-specific genetic factors shared between MDD and other psychiatric conditions, biases our view of genetic architecture of MDD, and limits our ability to identify pathways specific to MDD.Fundings Support for authors are detailed in Acknowledgements.