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High-throughput massively parallel reporter assays (MPRAs) and phenotype-rich in vivo transgenic mouse assays are two potentially complementary ways to study the impact of noncoding variants associated with psychiatric diseases. Here, we investigate the utility of combining these assays. Specifically, we carry out an MPRA in induced human neurons on over 50,000 sequences derived from fetal neuronal ATAC-seq datasets and enhancers validated in mouse assays. We also test the impact of over 20,000 variants, including synthetic mutations and 167 common variants associated with psychiatric disorders. We find a strong and specific correlation between MPRA and mouse neuronal enhancer activity. Four out of five tested variants with significant MPRA effects affected neuronal enhancer activity in mouse embryos. Mouse assays also reveal pleiotropic variant effects that could not be observed in MPRA. Our work provides a catalog of functional neuronal enhancers and variant effects and highlights the effectiveness of combining MPRAs and mouse transgenic assays.
MPRAs and in vivo transgenic mouse assays are two potentially complementary ways to assay the impact of noncoding variants. Here, authors find a strong and specific correlation between the assays in neural cells. Mouse assays also reveal pleiotropic effects not observed in MPRA.
Details
; Laboy Cintrón, Dianne 2 ; Keukeleire, Pia 3
; Schubach, Max 4
; Page, Nicholas F. 5 ; Georgakopoulos-Soares, Ilias 6
; Akiyama, Jennifer A. 1
; Plajzer-Frick, Ingrid 1 ; Novak, Catherine S. 1 ; Kato, Momoe 1 ; Hunter, Riana D. 1 ; von Maydell, Kianna 1 ; Barton, Sarah 1 ; Godfrey, Patrick 1 ; Beckman, Erik 1 ; Sanders, Stephan J. 7
; Kircher, Martin 8 ; Pennacchio, Len A. 1
; Ahituv, Nadav 2
1 Environmental Genomics & Systems Biology Division, Lawrence Berkeley National Laboratory, 94720, Berkeley, CA, USA (ROR: https://ror.org/02jbv0t02) (GRID: grid.184769.5) (ISNI: 0000 0001 2231 4551)
2 Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158, San Francisco, CA, USA (ROR: https://ror.org/043mz5j54) (GRID: grid.266102.1) (ISNI: 0000 0001 2297 6811); Institute for Human Genetics, University of California San Francisco, 94158, San Francisco, CA, USA (ROR: https://ror.org/043mz5j54) (GRID: grid.266102.1) (ISNI: 0000 0001 2297 6811)
3 Institute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck, 23562, Lübeck, Germany (ROR: https://ror.org/00t3r8h32) (GRID: grid.4562.5) (ISNI: 0000 0001 0057 2672)
4 Berlin Institute of Health at Charité – Universitätsmedizin Berlin, 10117, Berlin, Germany (ROR: https://ror.org/0493xsw21) (GRID: grid.484013.a)
5 Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 94158, San Francisco, CA, USA (ROR: https://ror.org/043mz5j54) (GRID: grid.266102.1) (ISNI: 0000 0001 2297 6811); Institute for Human Genetics, University of California San Francisco, 94158, San Francisco, CA, USA (ROR: https://ror.org/043mz5j54) (GRID: grid.266102.1) (ISNI: 0000 0001 2297 6811); Department of Psychiatry and Behavioral Sciences, Kavli Institute for Fundamental Neuroscience, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA (ROR: https://ror.org/043mz5j54) (GRID: grid.266102.1) (ISNI: 0000 0001 2297 6811)
6 Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, 17033, Hershey, PA, USA (ROR: https://ror.org/04p491231) (GRID: grid.29857.31) (ISNI: 0000 0001 2097 4281)
7 Institute for Human Genetics, University of California San Francisco, 94158, San Francisco, CA, USA (ROR: https://ror.org/043mz5j54) (GRID: grid.266102.1) (ISNI: 0000 0001 2297 6811); Department of Psychiatry and Behavioral Sciences, Kavli Institute for Fundamental Neuroscience, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA (ROR: https://ror.org/043mz5j54) (GRID: grid.266102.1) (ISNI: 0000 0001 2297 6811); Institute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, OX3 16 7TY, Oxford, UK (ROR: https://ror.org/052gg0110) (GRID: grid.4991.5) (ISNI: 0000 0004 1936 8948)
8 Institute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck, 23562, Lübeck, Germany (ROR: https://ror.org/00t3r8h32) (GRID: grid.4562.5) (ISNI: 0000 0001 0057 2672); Berlin Institute of Health at Charité – Universitätsmedizin Berlin, 10117, Berlin, Germany (ROR: https://ror.org/0493xsw21) (GRID: grid.484013.a)