Minimal phenotyping yields genome-wide association signals of low specificity for major depression

MDD Working Group of the Psychiatric Genomics Consortium

doi:10.1038/s41588-020-0594-5

Minimal phenotyping yields genome-wide association signals of low specificity for major depression

MDD Working Group of the Psychiatric Genomics Consortium

Medicine

Research output: Contribution to journal › Article › peer-review

202 Citations (Scopus)

Abstract

Minimal phenotyping refers to the reliance on the use of a small number of self-reported 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 for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.

Original language	English
Pages (from-to)	437-447
Number of pages	11
Journal	Nature Genetics
Volume	52
Issue number	4
DOIs	https://doi.org/10.1038/s41588-020-0594-5
Publication status	Published - Apr 1 2020

Bibliographical note

Funding Information:
We thank O. Weissbrod, A. Dahl, H. Shi and V. Zuber for insightful discussions. N.C. is supported by the ESPOD Fellowship from European Bioinformatics (EMBL-EBI) and Wellcome Sanger Institute. A.V. is supported by the Swedish Brain Foundation. C.M.L. and G.B. are funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. In the last 3 years, M.M.W. has received research funds from the US National Institute of Mental Health (NIMH), the Templeton Foundation and the Sackler Foundation and has received royalties for publication of books on interpersonal psychotherapy from Perseus Press and Oxford University Press, on other topics from the American Psychiatric Association Press and royalties on the social adjustment scale from Multihealth Systems. The CoLaus|PsyCoLaus study was and is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne and the Swiss National Science Foundation (grants 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401 and 33CS30-177535/1). The PGC has received major funding from the US NIMH and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320). This research was conducted using the UK Biobank resource under application no. 28709 and with the support and collaboration from all investigators who make up the MDD Working Group of the PGC (full list in the Supplementary Note). We are greatly indebted to the hundreds of thousands of individuals who have shared their life experiences with the UK Biobank and PGC investigators.

Funding Information:
C.M.L. is on the scientific advisory board of Myriad Neuroscience. H.J.G. has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm and Janssen Cilag as well as research funding from Fresenius Medical Care. B.W.J.H.P. has received (non-related) research grants from Jansen Research and Boehringer Ingelheim.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus Subject Areas

Genetics

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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10.1038/s41588-020-0594-5

Cite this

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title = "Minimal phenotyping yields genome-wide association signals of low specificity for major depression",

abstract = "Minimal phenotyping refers to the reliance on the use of a small number of self-reported 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 for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.",

author = "{MDD Working Group of the Psychiatric Genomics Consortium} and Na Cai and Revez, {Joana A.} and Adams, {Mark J.} and Andlauer, {Till F.M.} and Gerome Breen and Byrne, {Enda M.} and Clarke, {Toni Kim} and Forstner, {Andreas J.} and Grabe, {Hans J.} and Hamilton, {Steven P.} and Levinson, {Douglas F.} and Lewis, {Cathryn M.} and Glyn Lewis and Martin, {Nicholas G.} and Yuri Milaneschi and Ole Mors and Bertram M{\"u}ller-Myhsok and Penninx, {Brenda W.J.H.} and Perlis, {Roy H.} and Giorgio Pistis and Potash, {James B.} and Martin Preisig and Jianxin Shi and Smoller, {Jordan W.} and Fabien Streit and Henning Tiemeier and Rudolf Uher and {Van der Auwera}, Sandra and Alexander Viktorin and Weissman, {Myrna M.} and Kendler, {Kenneth S.} and Jonathan Flint",

note = "Funding Information: We thank O. Weissbrod, A. Dahl, H. Shi and V. Zuber for insightful discussions. N.C. is supported by the ESPOD Fellowship from European Bioinformatics (EMBL-EBI) and Wellcome Sanger Institute. A.V. is supported by the Swedish Brain Foundation. C.M.L. and G.B. are funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King{\textquoteright}s College London. In the last 3 years, M.M.W. has received research funds from the US National Institute of Mental Health (NIMH), the Templeton Foundation and the Sackler Foundation and has received royalties for publication of books on interpersonal psychotherapy from Perseus Press and Oxford University Press, on other topics from the American Psychiatric Association Press and royalties on the social adjustment scale from Multihealth Systems. The CoLaus|PsyCoLaus study was and is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne and the Swiss National Science Foundation (grants 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401 and 33CS30-177535/1). The PGC has received major funding from the US NIMH and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320). This research was conducted using the UK Biobank resource under application no. 28709 and with the support and collaboration from all investigators who make up the MDD Working Group of the PGC (full list in the Supplementary Note). We are greatly indebted to the hundreds of thousands of individuals who have shared their life experiences with the UK Biobank and PGC investigators. Funding Information: C.M.L. is on the scientific advisory board of Myriad Neuroscience. H.J.G. has received travel grants and speaker{\textquoteright}s honoraria from Fresenius Medical Care, Neuraxpharm and Janssen Cilag as well as research funding from Fresenius Medical Care. B.W.J.H.P. has received (non-related) research grants from Jansen Research and Boehringer Ingelheim. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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doi = "10.1038/s41588-020-0594-5",

language = "English",

volume = "52",

pages = "437--447",

journal = "Nature Genetics",

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T1 - Minimal phenotyping yields genome-wide association signals of low specificity for major depression

AU - MDD Working Group of the Psychiatric Genomics Consortium

AU - Cai, Na

AU - Revez, Joana A.

AU - Adams, Mark J.

AU - Andlauer, Till F.M.

AU - Breen, Gerome

AU - Byrne, Enda M.

AU - Clarke, Toni Kim

AU - Forstner, Andreas J.

AU - Grabe, Hans J.

AU - Hamilton, Steven P.

AU - Levinson, Douglas F.

AU - Lewis, Cathryn M.

AU - Lewis, Glyn

AU - Martin, Nicholas G.

AU - Milaneschi, Yuri

AU - Mors, Ole

AU - Müller-Myhsok, Bertram

AU - Penninx, Brenda W.J.H.

AU - Perlis, Roy H.

AU - Pistis, Giorgio

AU - Potash, James B.

AU - Preisig, Martin

AU - Shi, Jianxin

AU - Smoller, Jordan W.

AU - Streit, Fabien

AU - Tiemeier, Henning

AU - Uher, Rudolf

AU - Van der Auwera, Sandra

AU - Viktorin, Alexander

AU - Weissman, Myrna M.

AU - Kendler, Kenneth S.

AU - Flint, Jonathan

N1 - Funding Information: We thank O. Weissbrod, A. Dahl, H. Shi and V. Zuber for insightful discussions. N.C. is supported by the ESPOD Fellowship from European Bioinformatics (EMBL-EBI) and Wellcome Sanger Institute. A.V. is supported by the Swedish Brain Foundation. C.M.L. and G.B. are funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. In the last 3 years, M.M.W. has received research funds from the US National Institute of Mental Health (NIMH), the Templeton Foundation and the Sackler Foundation and has received royalties for publication of books on interpersonal psychotherapy from Perseus Press and Oxford University Press, on other topics from the American Psychiatric Association Press and royalties on the social adjustment scale from Multihealth Systems. The CoLaus|PsyCoLaus study was and is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne and the Swiss National Science Foundation (grants 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401 and 33CS30-177535/1). The PGC has received major funding from the US NIMH and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320). This research was conducted using the UK Biobank resource under application no. 28709 and with the support and collaboration from all investigators who make up the MDD Working Group of the PGC (full list in the Supplementary Note). We are greatly indebted to the hundreds of thousands of individuals who have shared their life experiences with the UK Biobank and PGC investigators. Funding Information: C.M.L. is on the scientific advisory board of Myriad Neuroscience. H.J.G. has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm and Janssen Cilag as well as research funding from Fresenius Medical Care. B.W.J.H.P. has received (non-related) research grants from Jansen Research and Boehringer Ingelheim. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Minimal phenotyping refers to the reliance on the use of a small number of self-reported 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 for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.

AB - Minimal phenotyping refers to the reliance on the use of a small number of self-reported 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 for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.

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Minimal phenotyping yields genome-wide association signals of low specificity for major depression

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

Access to Document

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