Minimal phenotyping yields GWAS hits of reduced specificity for major depression
Joana A Revez,
Mark J. Adams,
Till F. M. Andlauer,
Enda M. Byrne,
Andreas J. Forstner,
Hans J. Grabe,
Steven P. Hamilton,
Douglas F. Levinson,
Cathryn M. Lewis,
Nicholas G Martin,
Brenda WJH Penninx,
Roy H. Perlis,
James B. Potash,
Jordan W. Smoller,
Sandra Van der Auwera,
Myrna M. Weissman,
MDD Working Group of the Psychiatric Genomics Consortium,
Kenneth S. Kendler,
Posted 11 Oct 2018
bioRxiv DOI: 10.1101/440735
Posted 11 Oct 2018
Minimal phenotyping refers to the reliance on the use of a small number of self-report items 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%). This cannot be explained by differences in prevalence between definitions or including cases of lower liability to MDD in minimal phenotyping definitions of depression, but can be explained by misdiagnosis of those without depression or with related conditions as cases of depression. Depression defined by minimal phenotyping is as genetically correlated with strictly defined MDD (rG = 0.81, SE = 0.03) as it is with the personality trait neuroticism (rG = 0.84, SE = 0.05), a trait not defined by the cardinal symptoms of depression. While they both show similar shared genetic liability with neuroticism, a greater proportion of the genome contributes 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, while highly predictive polygenic risk scores can be generated from minimal phenotyping definitions of MDD, the predictive power can be explained entirely by the sample size used to generate the polygenic risk score, rather than specificity for MDD. 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 may impede our ability to identify pathways specific to MDD.
- Downloaded 1,843 times
- Download rankings, all-time:
- Site-wide: 4,456 out of 94,912
- In genetics: 321 out of 4,824
- Year to date:
- Site-wide: 8,510 out of 94,912
- Since beginning of last month:
- Site-wide: 20,112 out of 94,912
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!