Retrotransposon insertions associated with risk of neurologic and psychiatric diseases

Authors

• HW Ahn
• ZF Worman
• A Lechsinska
• LM Payer
• T Wang
• N Malik
• W Li
• KH Burns
• A Nath
• HL Levin

Abstract

Transposable elements (TEs) are active in neuronal cells raising the question whether TE insertions contribute to risk of neuropsychiatric disease. While genome wide association studies (GWAS) serve as a tool to discover genetic loci associated with neuropsychiatric diseases, unfortunately, GWAS do not directly detect structural variants such as TEs. To examine the role of TEs in psychiatric and neurologic disease we evaluate 17,000 polymorphic TEs and find 76 are in linkage disequilibrium with disease haplotypes (P < 10−6) defined by GWAS. From these 76 polymorphic TEs we identify causal candidates based on having insertions in genomic regions of regulatory chromatin and on having associations with altered gene expression in brain tissues. We show that lead candidate insertions have regulatory effects on gene expression in human neural stem cells, altering the activity of a minimal promoter. Taken together, we identify 10 polymorphic TE insertions that are potential candidates on par with other variants for having a causal role in neurologic and psychiatric disorders. We have CRISPR/Cas edited human iPSCs to generate presence or absence of candidate causal TEs. This will enable us to test the direct impact of the causal candidate TEs in a cell culture system. By comparing expression level of genes surrounding causal candidate TE insertions and examining epigenetic landscape of TE insertion sites in iPSCs as well as iPSCs differentiated into neuronal lineage cells, we will gain valuable insight on the contribution of our candidate causal TEs to their association with neuropsychiatric diseases.

Scientific Focus Area: Genetics and Genomics

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