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A candidate causal variant underlying both enhanced cognitive performance and increased risk of bipolar disorder

View ORCID ProfileSusan Q. Shen, Jeong Sook Kim-Han, Lin Cheng, Duo Xu, Omer Gokcumen, Andrew E.O. Hughes, Connie A. Myers, Joseph C. Corbo
doi: https://doi.org/10.1101/580258
Susan Q. Shen
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
4Department of Psychiatry, University of California San Francisco, San Francisco, CA
MD, PhD
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  • ORCID record for Susan Q. Shen
Jeong Sook Kim-Han
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
5Department of Pharmacology, Kirksville College of Osteopathic Medicine, A. T. Still University of Health Sciences, Kirksville, MO
PhD
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Lin Cheng
2School of Life Science, Peking University, Beijing, China
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Duo Xu
3Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY
6Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY
PhD
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Omer Gokcumen
3Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY
PhD
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Andrew E.O. Hughes
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
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Connie A. Myers
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
PhD
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Joseph C. Corbo
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
MD, PhD
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  • For correspondence: jcorbo@wustl.edu
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ABSTRACT

Bipolar disorder is a highly heritable mental illness, but the relevant genetic variants and molecular mechanisms are largely unknown. Recent GWASs have identified an intergenic region associated with both cognitive performance and bipolar disorder. This region contains dozens of putative fetal brain-specific enhancers and is located ∼0.7 Mb upstream of the neuronal transcription factor POU3F2. We identified a candidate causal variant, rs77910749, that falls within a highly conserved putative enhancer, LC1. This human-specific variant is a single-base deletion in a PAX6 binding site and is predicted to be functional. We hypothesized that rs77910749 alters LC1 activity and hence POU3F2 expression during neurodevelopment. Indeed, transgenic reporter mice demonstrated LC1 activity in the developing cerebral cortex and amygdala. Furthermore, ex vivo reporter assays in embryonic mouse brain and human iPSC-derived cerebral organoids revealed increased enhancer activity conferred by the variant. To probe the in vivo function of LC1, we deleted the orthologous mouse region, which resulted in amygdala-specific changes in Pou3f2 expression. Lastly, ‘humanized’ rs77910749 knock-in mice displayed behavioral defects in sensory gating, an amygdala-dependent endophenotype seen in patients with bipolar disorder. Our study suggests a molecular mechanism underlying the long-speculated link between enhanced cognitive performance and neuropsychiatric disease.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted October 28, 2021.
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A candidate causal variant underlying both enhanced cognitive performance and increased risk of bipolar disorder
Susan Q. Shen, Jeong Sook Kim-Han, Lin Cheng, Duo Xu, Omer Gokcumen, Andrew E.O. Hughes, Connie A. Myers, Joseph C. Corbo
bioRxiv 580258; doi: https://doi.org/10.1101/580258
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A candidate causal variant underlying both enhanced cognitive performance and increased risk of bipolar disorder
Susan Q. Shen, Jeong Sook Kim-Han, Lin Cheng, Duo Xu, Omer Gokcumen, Andrew E.O. Hughes, Connie A. Myers, Joseph C. Corbo
bioRxiv 580258; doi: https://doi.org/10.1101/580258

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