Article open access publication

Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

Nature Genetics, Springer Nature, ISSN 1061-4036

Volume 50, 3, 2018

DOI:10.1038/s41588-018-0059-2, Dimensions: pub.1101216525, PMC: PMC5918692, PMID: 29483656,

Authors

Ripke, Stephan (2) (3)
Han, Jun (1)
Agerbo, Esben (15) (16)
Als, Thomas D. (15) (16)
Andreassen, Ole A. (17) (18)
Djurovic, Srdjan (18) (20)
Grove, Jakob (15) (16)
Hougaard, David M. (15) (19)
Mattheisen, Manuel (15) (16)
Mors, Ole (15) (24)
Nordentoft, Merete (15) (25)
Werge, Thomas (15) (25) (31)
Rujescu, Dan (33) (34)

* Corresponding author

Affiliations

Organisations

  1. (1) Cardiff University, grid.5600.3
  2. (2) Charité, grid.6363.0
  3. (3) Massachusetts General Hospital, grid.32224.35
  4. (4) King's College London, grid.13097.3c
  5. (5) Broad Institute, grid.66859.34
  6. (6) University of Adelaide, grid.1010.0
  7. (7) University of Queensland, grid.1003.2
  8. (8) University of Münster, grid.5949.1
  9. (9) University of Edinburgh, grid.4305.2
  10. (10) QIMR Berghofer Medical Research Institute, grid.1049.c
  11. (11) University of Vigo, grid.6312.6
  12. (12) University of California, Los Angeles, grid.19006.3e
  13. (13) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  14. (14) University of Oviedo, grid.10863.3c
  15. (15) Lundbeck Foundation, grid.452548.a
  16. (16) Aarhus University, grid.7048.b, AU
  17. (17) University of Oslo, grid.5510.1
  18. (18) Oslo University Hospital, grid.55325.34
  19. (19) State Serum Institute, grid.6203.7
  20. (20) University of Bergen, grid.7914.b
  21. (21) PHI University Psychiatric Clinic - Skopje, grid.452081.a
  22. (22) Department of Clinical Genetics, Mental Health Research Center, Moscow, Russia
  23. (23) Diakonhjemmet Hospital, grid.413684.c
  24. (24) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  25. (25) University of Copenhagen, grid.5254.6, KU
  26. (26) University of Belgrade, grid.7149.b
  27. (27) National University Hospital of Iceland, grid.410540.4
  28. (28) Tbilisi State Medical University, grid.412274.6
  29. (29) deCODE Genetics (Iceland), grid.421812.c
  30. (30) University of Verona, grid.5611.3
  31. (31) Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
  32. (32) Eli Lilly (United Kingdom), grid.418786.4
  33. (33) Ludwig Maximilian University of Munich, grid.5252.0
  34. (34) Martin Luther University Halle-Wittenberg, grid.9018.0

Description

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

Funders

Research Categories

Main Subject Area

Fields of Research

Links & Metrics

NORA University Profiles

Aarhus University

University of Copenhagen

Danish Open Access Indicator

2018: Realized

Research area: Medicine

Danish Bibliometrics Indicator

2018: Level 3

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 453

Field Citation Ratio (FCR): 145.2

Relative Citation ratio (RCR): 37.45

Open Access Info

Green, Published