Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses

Thomas D. Als; Mitja I. Kurki; Jakob Grove; Georgios Voloudakis; Karen Therrien; Elisa Tasanko; Trine Tollerup Nielsen; Joonas Naamanka; Kumar Veerapen; Daniel F. Levey; Jaroslav Bendl; Jonas Bybjerg-Grauholm; Biao Zeng; Ditte Demontis; Anders Rosengren; Georgios Athanasiadis; Marie Bækved-Hansen; Per Qvist; G. Bragi Walters; Thorgeir Thorgeirsson; Hreinn Stefánsson; Katherine L. Musliner; Veera M. Rajagopal; Leila Farajzadeh; Janne Thirstrup; Bjarni J. Vilhjálmsson; John J. McGrath; Manuel Mattheisen; Sandra Meier; Esben Agerbo; Kári Stefánsson; Merete Nordentoft; Thomas Werge; David M. Hougaard; Preben B. Mortensen; Murray B. Stein; Joel Gelernter; Iiris Hovatta; Panos Roussos; Mark J. Daly; Ole Mors; Aarno Palotie; Anders D. Børglum

doi:10.1038/s41591-023-02352-1

Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses

Thomas D. Als^*, Mitja I. Kurki, Jakob Grove, Georgios Voloudakis, Karen Therrien, Elisa Tasanko, Trine Tollerup Nielsen, Joonas Naamanka, Kumar Veerapen, Daniel F. Levey, Jaroslav Bendl, Jonas Bybjerg-Grauholm, Biao Zeng, Ditte Demontis, Anders Rosengren, Georgios Athanasiadis, Marie Bækved-Hansen, Per Qvist, G. Bragi Walters, Thorgeir ThorgeirssonHreinn Stefánsson, Katherine L. Musliner, Veera M. Rajagopal, Leila Farajzadeh, Janne Thirstrup, Bjarni J. Vilhjálmsson, John J. McGrath, Manuel Mattheisen, Sandra Meier, Esben Agerbo, Kári Stefánsson, Merete Nordentoft, Thomas Werge, David M. Hougaard, Preben B. Mortensen, Murray B. Stein, Joel Gelernter, Iiris Hovatta, Panos Roussos, Mark J. Daly, Ole Mors, Aarno Palotie, Anders D. Børglum^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.

Original language	English
Journal	Nature Medicine
Volume	29
Issue	7
Pages (from-to)	1832-1844
Number of pages	13
ISSN	1078-8956
DOIs	https://doi.org/10.1038/s41591-023-02352-1
Publication status	Published - Jul 2023

Access to Document

10.1038/s41591-023-02352-1

Cite this

Als, T. D., Kurki, M. I., Grove, J., Voloudakis, G., Therrien, K., Tasanko, E., Nielsen, T. T., Naamanka, J., Veerapen, K., Levey, D. F., Bendl, J., Bybjerg-Grauholm, J., Zeng, B., Demontis, D., Rosengren, A., Athanasiadis, G., Bækved-Hansen, M., Qvist, P., Bragi Walters, G., ... Børglum, A. D. (2023). Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses. Nature Medicine, 29(7), 1832-1844. https://doi.org/10.1038/s41591-023-02352-1

@article{8efa5a83e6a8470691fc3aca0420d253,

title = "Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses",

abstract = "Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.",

author = "Als, {Thomas D.} and Kurki, {Mitja I.} and Jakob Grove and Georgios Voloudakis and Karen Therrien and Elisa Tasanko and Nielsen, {Trine Tollerup} and Joonas Naamanka and Kumar Veerapen and Levey, {Daniel F.} and Jaroslav Bendl and Jonas Bybjerg-Grauholm and Biao Zeng and Ditte Demontis and Anders Rosengren and Georgios Athanasiadis and Marie B{\ae}kved-Hansen and Per Qvist and {Bragi Walters}, G. and Thorgeir Thorgeirsson and Hreinn Stef{\'a}nsson and Musliner, {Katherine L.} and Rajagopal, {Veera M.} and Leila Farajzadeh and Janne Thirstrup and Vilhj{\'a}lmsson, {Bjarni J.} and McGrath, {John J.} and Manuel Mattheisen and Sandra Meier and Esben Agerbo and K{\'a}ri Stef{\'a}nsson and Merete Nordentoft and Thomas Werge and Hougaard, {David M.} and Mortensen, {Preben B.} and Stein, {Murray B.} and Joel Gelernter and Iiris Hovatta and Panos Roussos and Daly, {Mark J.} and Ole Mors and Aarno Palotie and B{\o}rglum, {Anders D.}",

year = "2023",

month = jul,

doi = "10.1038/s41591-023-02352-1",

language = "English",

volume = "29",

pages = "1832--1844",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "7",

}

Als, TD, Kurki, MI, Grove, J, Voloudakis, G, Therrien, K, Tasanko, E, Nielsen, TT, Naamanka, J, Veerapen, K, Levey, DF, Bendl, J, Bybjerg-Grauholm, J, Zeng, B, Demontis, D, Rosengren, A, Athanasiadis, G, Bækved-Hansen, M, Qvist, P, Bragi Walters, G, Thorgeirsson, T, Stefánsson, H, Musliner, KL, Rajagopal, VM, Farajzadeh, L, Thirstrup, J, Vilhjálmsson, BJ , McGrath, JJ, Mattheisen, M, Meier, S, Agerbo, E, Stefánsson, K, Nordentoft, M, Werge, T, Hougaard, DM, Mortensen, PB, Stein, MB, Gelernter, J, Hovatta, I, Roussos, P, Daly, MJ, Mors, O, Palotie, A & Børglum, AD 2023, 'Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses', Nature Medicine, vol. 29, no. 7, pp. 1832-1844. https://doi.org/10.1038/s41591-023-02352-1

Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses. / Als, Thomas D.; Kurki, Mitja I.; Grove, Jakob et al.
In: Nature Medicine, Vol. 29, No. 7, 07.2023, p. 1832-1844.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses

AU - Als, Thomas D.

AU - Kurki, Mitja I.

AU - Grove, Jakob

AU - Voloudakis, Georgios

AU - Therrien, Karen

AU - Tasanko, Elisa

AU - Nielsen, Trine Tollerup

AU - Naamanka, Joonas

AU - Veerapen, Kumar

AU - Levey, Daniel F.

AU - Bendl, Jaroslav

AU - Bybjerg-Grauholm, Jonas

AU - Zeng, Biao

AU - Demontis, Ditte

AU - Rosengren, Anders

AU - Athanasiadis, Georgios

AU - Bækved-Hansen, Marie

AU - Qvist, Per

AU - Bragi Walters, G.

AU - Thorgeirsson, Thorgeir

AU - Stefánsson, Hreinn

AU - Musliner, Katherine L.

AU - Rajagopal, Veera M.

AU - Farajzadeh, Leila

AU - Thirstrup, Janne

AU - Vilhjálmsson, Bjarni J.

AU - McGrath, John J.

AU - Mattheisen, Manuel

AU - Meier, Sandra

AU - Agerbo, Esben

AU - Stefánsson, Kári

AU - Nordentoft, Merete

AU - Werge, Thomas

AU - Hougaard, David M.

AU - Mortensen, Preben B.

AU - Stein, Murray B.

AU - Gelernter, Joel

AU - Hovatta, Iiris

AU - Roussos, Panos

AU - Daly, Mark J.

AU - Mors, Ole

AU - Palotie, Aarno

AU - Børglum, Anders D.

PY - 2023/7

Y1 - 2023/7

N2 - Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.

AB - Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.

UR - http://www.scopus.com/inward/record.url?scp=85165277821&partnerID=8YFLogxK

U2 - 10.1038/s41591-023-02352-1

DO - 10.1038/s41591-023-02352-1

M3 - Journal article

C2 - 37464041

AN - SCOPUS:85165277821

SN - 1078-8956

VL - 29

SP - 1832

EP - 1844

JO - Nature Medicine

JF - Nature Medicine

IS - 7

ER -

Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses

Abstract

Access to Document

Other files and links

Fingerprint

Cite this