RT Journal Article
SR Electronic
T1 A candidate causal variant underlying both enhanced cognitive performance and increased risk of bipolar disorder
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 580258
DO 10.1101/580258
A1 Susan Q. Shen
A1 Jeong Sook Kim-Han
A1 Lin Cheng
A1 Duo Xu
A1 Omer Gokcumen
A1 Andrew E.O. Hughes
A1 Connie A. Myers
A1 Joseph C. Corbo
YR 2021
UL http://biorxiv.org/content/early/2021/10/28/580258.abstract
AB 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 StatementThe authors have declared no competing interest.