Genetic influences on cell type specific gene expression and splicing during neurogenesis elucidate regulatory mechanisms of brain traits

Aygün, N.; Elwell, A. L.; Liang, D.; Lafferty, M. J.; Cheek, K. E.; Courtney, K. P.; Mory, J.; Hadden-Ford, E.; Krupa, O.; de la Torre-Ubieta, L.; Geschwind, D. H.; Love, M. I.; Stein, J. L.

doi:10.1101/2020.10.21.349019

bioRxiv · 10.1101/2020.10.21.349019

Genetic influences on cell type specific gene expression and splicing during neurogenesis elucidate regulatory mechanisms of brain traits

Aygün, N.·Elwell, A. L.·Liang, D.·Lafferty, M. J.·Cheek, K. E.·Courtney, K. P.·Mory, J.·Hadden-Ford, E.·Krupa, O.·de la Torre-Ubieta, L.·Geschwind, D. H.·Love, M. I.·Stein, J. L.

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Abstract

Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map expression quantitative trait loci (eQTLs), splicing QTLs (sQTLs), and allele specific expression in primary human neural progenitors (n=85) and their sorted neuronal progeny (n=74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome wide association, we uncover cell-type specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations of cortical area and educational attainment.

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Aygün, N., Elwell, A. L., Liang, D., Lafferty, M. J., Cheek, K. E., Courtney, K. P., Mory, J., Hadden-Ford, E., Krupa, O., de la Torre-Ubieta, L., Geschwind, D. H., Love, M. I., Stein, J. L.. 2020-10-22. Genetic influences on cell type specific gene expression and splicing during neurogenesis elucidate regulatory mechanisms of brain traits. https://doi.org/10.1101/2020.10.21.349019

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