Minimal Phenotyping Yields Genome-Wide Association Signals of Low Specificity for Major Depression

Cai, NaRevez, Joana A.Adams, Mark J.Andlauer, Till F. M.Breen, GeromeByrne, Enda M.Clarke, Toni-KimForstner, Andreas J.Grabe, Hans J.Hamilton, Steven P.Levinson, Douglas F.Lewis, Cathryn M.Lewis, GlynMartin, Nicholas G.Milaneschi, YuriMors, OleMuller-Myhsok, BertramPenninx, Brenda W. J. H.Perlis, Roy H.Pistis, GiorgioPotash, James B.Preisig, MartinShi, JianxinSmoller, Jordan W.Streit, FabienTiemeier, HenningUher, RudolfVan der Auwera, SandraViktorin, AlexanderWeissman, Myrna M.Kendler, Kenneth S.Flint, Jonathan2022-06-022020-03-30Cai, Na, Revez, Joana A, Adams, Mark J, Andlauer, Till F. M, Breen, Gerome, Byrne, Enda M, Clarke, Toni-Kim, Forstner, Andreas J, Grabe, Hans J, Hamilton, Steven P, Levinson, Douglas F, Lewis, Cathryn M, Lewis, Glyn, Martin, Nicholas G, Milaneschi, Yuri, Mors, Ole, Mueller-Myhsok, Bertram, Penninx, Brenda W. J. H, Perlis, Roy H, Pistis, Giorgio, Potash, James B, Preisig, Martin, Shi, Jianxin, Smoller, Jordan W, Streit, Fabien, Tiemeier, Henning, Uher, Rudolf, Van Der Auwera, Sandra, Viktorin, Alexander, Weissman, Myrna M, Kendler, Kenneth S, and Flint, Jonathan. "Minimal Phenotyping Yields Genome-wide Association Signals of Low Specificity for Major Depression." Nature Genetics 52, no. 4 (2020): 437-47.https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37371856Minimal phenotyping refers to the reliance on the use of a small number of self-report items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined Major Depressive Disorder (MDD): the former 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 strictly-defined MDD. GWAS on minimal phenotyping definitions identify loci that are not specific to MDD, and though it can generate highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than specificity for MDD. Our results reveal reliance on results from minimal phenotyping may bias our views of the genetic architecture of MDD and impede our ability to identify pathways specific to MDD.en-USMinimal Phenotyping Yields Genome-Wide Association Signals of Low Specificity for Major DepressionJournal Article2022-06-02