Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Duncan S Palmer; Daniel P Howrigan; Sinéad B Chapman; Rolf Adolfsson; Nick Bass; Douglas Blackwood; Marco P M Boks; Chia-Yen Chen; Claire Churchhouse; Aiden P Corvin; Nicholas Craddock; David Curtis; Arianna Di Florio; Faith Dickerson; Nelson B Freimer; Fernando S Goes; Xiaoming Jia; Ian Jones; Lisa Jones; Lina Jonsson; Rene S Kahn; Mikael Landén; Adam E Locke; Andrew M McIntosh; Andrew McQuillin; Derek W Morris; Michael C O'Donovan; Roel A Ophoff; Michael J Owen; Nancy L Pedersen; Danielle Posthuma; Andreas Reif; Neil Risch; Catherine Schaefer; Laura Scott; Tarjinder Singh; Jordan W Smoller; Matthew Solomonson; David St Clair; Eli A Stahl; Annabel Vreeker; James T R Walters; Weiqing Wang; Nicholas A Watts; Robert Yolken; Peter P Zandi; Benjamin M Neale

doi:10.1038/s41588-022-01034-x

Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Nat Genet. 2022 May;54(5):541-547. doi: 10.1038/s41588-022-01034-x. Epub 2022 Apr 11.

Authors

Duncan S Palmer^{1

2}, Daniel P Howrigan^{3

4}, Sinéad B Chapman⁴, Rolf Adolfsson⁵, Nick Bass⁶, Douglas Blackwood⁷, Marco P M Boks⁸, Chia-Yen Chen^{3

4

9}, Claire Churchhouse^{3

4

10}, Aiden P Corvin¹¹, Nicholas Craddock¹², David Curtis^{13

14}, Arianna Di Florio¹⁵, Faith Dickerson¹⁶, Nelson B Freimer^{17

18}, Fernando S Goes¹⁹, Xiaoming Jia²⁰, Ian Jones^{12

21}, Lisa Jones²², Lina Jonsson^{23

24}, Rene S Kahn²⁵, Mikael Landén^{23

26}, Adam E Locke²⁷, Andrew M McIntosh⁷, Andrew McQuillin⁶, Derek W Morris²⁸, Michael C O'Donovan¹², Roel A Ophoff^{17

18

29}, Michael J Owen¹², Nancy L Pedersen²⁶, Danielle Posthuma³⁰, Andreas Reif³¹, Neil Risch^{32

33}, Catherine Schaefer³³, Laura Scott³⁴, Tarjinder Singh^{3

4}, Jordan W Smoller^{35

36}, Matthew Solomonson¹⁰, David St Clair³⁷, Eli A Stahl³⁸, Annabel Vreeker³⁹, James T R Walters¹², Weiqing Wang³⁸, Nicholas A Watts^{3

10}, Robert Yolken⁴⁰, Peter P Zandi¹⁹, Benjamin M Neale^{41

42

43}

Affiliations

¹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected].
² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
³ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Department of Clinical Sciences, Psychiatry, Umea University, Umea, Sweden.
⁶ Division of Psychiatry, University College London, London, UK.
⁷ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
⁸ Department of Psychiatry, Brain Center UMC Utrecht, Utrecht, the Netherlands.
⁹ Biogen, Cambridge, MA, USA.
¹⁰ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Trinity College Dublin, Dublin, Ireland.
¹² MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
¹³ UCL Genetics Institute, University College London, London, UK.
¹⁴ Centre for Psychiatry, Queen Mary University of London, London, UK.
¹⁵ Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
¹⁶ Sheppard Pratt, Baltimore, MD, USA.
¹⁷ Department of Psychiatry and Biobehavioral Science, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁸ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁰ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
²¹ National Centre for Mental Health, Division of Psychiatry and Clinical Neurosciences, Cardiff University, Cardiff, UK.
²² Department of Psychological Medicine, University of Worcester, Worcester, UK.
²³ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁴ Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁵ Division of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁷ Division of Genomics & Bioinformatics and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
²⁸ Centre for Neuroimaging, Cognition and Genomics, Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
²⁹ Department of Psychiatry, Erasmus Medical Center, Erasmus University, Rotterdam, the Netherlands.
³⁰ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, the Netherlands.
³¹ Department of Psychiatry, Psychosomatic Medicine and Psychiatry, University Hospital Frankfurt - Goethe University, Frankfurt, Germany.
³² Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
³³ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
³⁴ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
³⁵ Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
³⁶ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
³⁷ Institute for Medical Sciences, University of Aberdeen, Aberdeen, UK.
³⁸ Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁹ Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC Sophia Children Hospital, Erasmus University, Rotterdam, the Netherlands.
⁴⁰ Stanley Division of Developmental Neurovirology, Johns Hopkins University, Baltimore, MD, USA.
⁴¹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected].
⁴² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁴³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].

Abstract

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10^-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

A Kinase Anchor Proteins / genetics
Bipolar Disorder* / genetics
Exome / genetics
Exome Sequencing
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Schizophrenia* / genetics

Substances

A Kinase Anchor Proteins
AKAP11 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding