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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

  • 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
  • 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
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.
OriginalsprogEngelsk
TidsskriftNature Medicine
Vol/bind29
Udgave nummer7
Sider (fra-til)1832-1844
Antal sider13
ISSN1078-8956
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the EU H2020 Program (grant no. 667302, ‘CoCA’), National Institutes of Health/National Institute of Mental Health (1U01MH109514-01 and 1R01MH124851-01 to A.D.B.) and the universities and university hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for the handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility (https://genome.au.dk/) was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). We thank the research participants and employees of 23andMe, Inc. for making this work possible. We thank all members of the iPSYCH-Broad Consortium for their efforts and collaborative spirit. The team at the Center for Disease Neurogenomics at the Icahn School of Medicine at Mount Sinai was supported by the National Institutes of Health (K08MH122911 to G.V.; T32MH087004 to K.T.; and R01MH125246, R01AG067025, U01MH116442 and R01MH109677 to P.R.). D.F.L. was funded by a Veterans Affairs Office of Research and Development Career Development Award (IK2BX005058). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funding Information:
The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the EU H2020 Program (grant no. 667302, ‘CoCA’), National Institutes of Health/National Institute of Mental Health (1U01MH109514-01 and 1R01MH124851-01 to A.D.B.) and the universities and university hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for the handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility ( https://genome.au.dk/ ) was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). We thank the research participants and employees of 23andMe, Inc. for making this work possible. We thank all members of the iPSYCH-Broad Consortium for their efforts and collaborative spirit. The team at the Center for Disease Neurogenomics at the Icahn School of Medicine at Mount Sinai was supported by the National Institutes of Health (K08MH122911 to G.V.; T32MH087004 to K.T.; and R01MH125246, R01AG067025, U01MH116442 and R01MH109677 to P.R.). D.F.L. was funded by a Veterans Affairs Office of Research and Development Career Development Award (IK2BX005058). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

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