Polygenic interactions with environmental adversity in the aetiology of major depressive disorder

N. Mullins; R. A. Power; H Fisher; K. B. Hanscombe; J. Euesden; R. Iniesta; D. F. Levinson; M. M. Weissman; J. B. Potash; J. Shi; R. Uher; S. Cohen-Woods; M. Rivera; L. Jones; I. Jones; N. Craddock; M. J. Owen; A. Korszun; I. W. Craig; A. E. Farmer; P. McGuffin; G. Breen; C. M. Lewis

doi:10.1017/S0033291715002172

Polygenic interactions with environmental adversity in the aetiology of major depressive disorder

N. Mullins^*, R. A. Power, H Fisher, K. B. Hanscombe, J. Euesden, R. Iniesta, D. F. Levinson, M. M. Weissman, J. B. Potash, J. Shi, R. Uher, S. Cohen-Woods, M. Rivera, L. Jones, I. Jones, N. Craddock, M. J. Owen, A. Korszun, I. W. Craig, A. E. FarmerP. McGuffin, G. Breen, C. M. Lewis

^*Corresponding author for this work

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Abstract

BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.

METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.

RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10-6). SLEs and CT were also associated with MDD status (p = 2.19 × 10-4 and p = 5.12 × 10-20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.

CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

Original language	English
Pages (from-to)	759-770
Number of pages	12
Journal	Psychological Medicine
Volume	46
Issue number	4
Early online date	3 Nov 2015
DOIs	https://doi.org/10.1017/S0033291715002172
Publication status	Published - Mar 2016

Keywords

Depression
gene-environment interactions
genetics
polygenic risk scoring

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Polygenic interactions with environmental_MULLINS_Acc22Sep2015Epub3Nov2015_GOLD VoR(CC BY)Final published version, 425 KBLicence: CC BY

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Mullins, N., Power, R. A., Fisher, H., Hanscombe, K. B., Euesden, J., Iniesta, R., Levinson, D. F., Weissman, M. M., Potash, J. B., Shi, J., Uher, R., Cohen-Woods, S., Rivera, M., Jones, L., Jones, I., Craddock, N., Owen, M. J., Korszun, A., Craig, I. W., ... Lewis, C. M. (2016). Polygenic interactions with environmental adversity in the aetiology of major depressive disorder. Psychological Medicine, 46(4), 759-770. https://doi.org/10.1017/S0033291715002172

@article{c36e672de05c438691442c58eb9fcde0,

title = "Polygenic interactions with environmental adversity in the aetiology of major depressive disorder",

abstract = "BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10-6). SLEs and CT were also associated with MDD status (p = 2.19 × 10-4 and p = 5.12 × 10-20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.",

keywords = "Depression, gene-environment interactions, genetics, polygenic risk scoring",

author = "N. Mullins and Power, {R. A.} and H Fisher and Hanscombe, {K. B.} and J. Euesden and R. Iniesta and Levinson, {D. F.} and Weissman, {M. M.} and Potash, {J. B.} and J. Shi and R. Uher and S. Cohen-Woods and M. Rivera and L. Jones and I. Jones and N. Craddock and Owen, {M. J.} and A. Korszun and Craig, {I. W.} and Farmer, {A. E.} and P. McGuffin and G. Breen and Lewis, {C. M.}",

year = "2016",

month = mar,

doi = "10.1017/S0033291715002172",

language = "English",

volume = "46",

pages = "759--770",

journal = "Psychological Medicine",

issn = "0033-2917",

publisher = "Cambridge University Press",

number = "4",

}

Mullins, N , Power, RA , Fisher, H, Hanscombe, KB, Euesden, J , Iniesta, R, Levinson, DF, Weissman, MM, Potash, JB, Shi, J, Uher, R, Cohen-Woods, S, Rivera, M, Jones, L, Jones, I, Craddock, N, Owen, MJ, Korszun, A, Craig, IW , Farmer, AE , McGuffin, P , Breen, G & Lewis, CM 2016, 'Polygenic interactions with environmental adversity in the aetiology of major depressive disorder', Psychological Medicine, vol. 46, no. 4, pp. 759-770. https://doi.org/10.1017/S0033291715002172

TY - JOUR

T1 - Polygenic interactions with environmental adversity in the aetiology of major depressive disorder

AU - Mullins, N.

AU - Power, R. A.

AU - Fisher, H

AU - Hanscombe, K. B.

AU - Euesden, J.

AU - Iniesta, R.

AU - Levinson, D. F.

AU - Weissman, M. M.

AU - Potash, J. B.

AU - Shi, J.

AU - Uher, R.

AU - Cohen-Woods, S.

AU - Rivera, M.

AU - Jones, L.

AU - Jones, I.

AU - Craddock, N.

AU - Owen, M. J.

AU - Korszun, A.

AU - Craig, I. W.

AU - Farmer, A. E.

AU - McGuffin, P.

AU - Breen, G.

AU - Lewis, C. M.

PY - 2016/3

Y1 - 2016/3

N2 - BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10-6). SLEs and CT were also associated with MDD status (p = 2.19 × 10-4 and p = 5.12 × 10-20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

AB - BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10-6). SLEs and CT were also associated with MDD status (p = 2.19 × 10-4 and p = 5.12 × 10-20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

KW - Depression

KW - gene-environment interactions

KW - genetics

KW - polygenic risk scoring

UR - http://www.scopus.com/inward/record.url?scp=84958107970&partnerID=8YFLogxK

U2 - 10.1017/S0033291715002172

DO - 10.1017/S0033291715002172

M3 - Article

C2 - 26526099

AN - SCOPUS:84958107970

SN - 0033-2917

VL - 46

SP - 759

EP - 770

JO - Psychological Medicine

JF - Psychological Medicine

IS - 4

ER -

Polygenic interactions with environmental adversity in the aetiology of major depressive disorder

Abstract

Keywords

UN SDGs

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