Abstract
Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development. Here we identify common variants that alter gene expression (expression quantitative trait loci [eQTLs]) constantly across development or predominantly during prenatal or postnatal stages. Both “constant” and “temporal-predominant” eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology.
| Original language | English |
|---|---|
| Article number | 107489 |
| Journal | Cell Reports |
| Volume | 31 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2020 Apr 7 |
Keywords
- BrainVar
- DLPFC
- LOC101926933 RP11-298I3.1 AL132780.1 ENSG00000257285
- PsychENCODE
- RHEBL1
- dorsolateral prefrontal cortex
- fetal transition
- mTOR
- prenatal eQTL
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex. / Werling, Donna M.; Pochareddy, Sirisha; Choi, Jinmyung et al.
In: Cell Reports, Vol. 31, No. 1, 107489, 07.04.2020.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex
AU - Werling, Donna M.
AU - Pochareddy, Sirisha
AU - Choi, Jinmyung
AU - An, Joon Yong
AU - Sheppard, Brooke
AU - Peng, Minshi
AU - Li, Zhen
AU - Dastmalchi, Claudia
AU - Santpere, Gabriel
AU - Sousa, André M.M.
AU - Tebbenkamp, Andrew T.N.
AU - Kaur, Navjot
AU - Gulden, Forrest O.
AU - Breen, Michael S.
AU - Liang, Lindsay
AU - Gilson, Michael C.
AU - Zhao, Xuefang
AU - Dong, Shan
AU - Klei, Lambertus
AU - Cicek, A. Ercument
AU - Buxbaum, Joseph D.
AU - Adle-Biassette, Homa
AU - Thomas, Jean Leon
AU - Aldinger, Kimberly A.
AU - O'Day, Diana R.
AU - Glass, Ian A.
AU - Zaitlen, Noah A.
AU - Talkowski, Michael E.
AU - Roeder, Kathryn
AU - State, Matthew W.
AU - Devlin, Bernie
AU - Sanders, Stephan J.
AU - Sestan, Nenad
N1 - Funding Information: Data were generated as part of the PsychENCODE Consortium, supported by U01MH103339, U01MH103365, U01MH103392, U01MH103340, U01MH103346, R01MH105472, R01MH094714, R01MH105898, R21MH102791, R21MH105881, R21MH103877, and P50MH106934 awarded to Schahram Akbarian (Icahn School of Medicine at Mount Sinai), Gregory Crawford (Duke), Stella Dracheva (Icahn School of Medicine at Mount Sinai), Peggy Farnham (USC), Mark Gerstein (Yale), Daniel Geschwind (UCLA), Thomas M. Hyde (LIBD), Andrew Jaffe (LIBD), James A. Knowles (USC), Chunyu Liu (UIC), Dalila Pinto (Icahn School of Medicine at Mount Sinai), Nenad Sestan (Yale), Pamela Sklar (Icahn School of Medicine at Mount Sinai), Matthew State (UCSF), Patrick Sullivan (UNC), Flora Vaccarino (Yale), Sherman Weissman (Yale), Kevin White (UChicago), and Peter Zandi (JHU). This work was supported by funding provided by Autism Science Foundation postdoctoral fellowships (to D.W. and J.-Y.A.) and a research award (to S.J.S.); Simons Foundation Autism Research Initiative (SFARI) grants 574598 (to S.J.S.), 402281 (to S.J.S., M.W.S., B.D., and K.R.), and 573206 (to M.E.T.); National Institute for Mental Health (NIMH) grants R01 MH109901 (to S.J.S. and M.W.S.), R01 MH110928 (to S.J.S. and M.W.S.), U01 MH103339 (to M.W.S.), R01 MH111662 (to S.J.S. and M.W.S.), U01 MH105575 (to M.W.S.), U01 MH106874 (to N.S.), P50 MH106934 (to N.S.), R01 MH109904 (to N.S.), R01 MH110926 (to N.S.), U01 MH116488 (to N.S.), R37 MH057881 (to B.D.), and R01 MH115957 (to M.E.T.); National Institute of Child Health and Human Development (NICHD) grants R24 HD000836 (to I.A.G.), R01 HD081256 (to M.E.T.), and R01 HD096326 (to M.E.T.); National Heart, Lung, and Blood Institute (NHLBI) grant K25HL121295 (to N.A.Z.); National Human Genome Research Institute (NHGRI) grants U01HG009080 (to N.A.Z.) and R01HG006399 (to N.A.Z.); National Cancer Institute (NCI) grant R01CA227237 (to N.A.Z.); National Institute of Dental and Craniofacial Research (NIDCR) grant R03DE025665 (to N.A.Z.); United States Department of Defense (DoD) grant W81XWH-16-2-0018 (to N.A.Z.); and National Research Foundation of Korea grant 2019M3E5D3073568 (to J.-Y.A.). The project that gave rise to these results also received the support of a fellowship from “la Caixa” Foundation ( ID 100010434 to G.S.). The fellowship code is LCF/BQ/PI19/11690010 . We thank Thomas Lehner, Anjené Addington, Geetha Senthil, and Alexander Arguello at the NIMH for supporting the PsychENCODE Consortium, the Yale Center for Genome Analysis for generating the RNA-seq data, GENEWIZ for generating the WGS data, and Sentieon for use of a computationally efficient implementation of GATK Haplotype Caller. Funding Information: Data were generated as part of the PsychENCODE Consortium, supported by U01MH103339, U01MH103365, U01MH103392, U01MH103340, U01MH103346, R01MH105472, R01MH094714, R01MH105898, R21MH102791, R21MH105881, R21MH103877, and P50MH106934 awarded to Schahram Akbarian (Icahn School of Medicine at Mount Sinai), Gregory Crawford (Duke), Stella Dracheva (Icahn School of Medicine at Mount Sinai), Peggy Farnham (USC), Mark Gerstein (Yale), Daniel Geschwind (UCLA), Thomas M. Hyde (LIBD), Andrew Jaffe (LIBD), James A. Knowles (USC), Chunyu Liu (UIC), Dalila Pinto (Icahn School of Medicine at Mount Sinai), Nenad Sestan (Yale), Pamela Sklar (Icahn School of Medicine at Mount Sinai), Matthew State (UCSF), Patrick Sullivan (UNC), Flora Vaccarino (Yale), Sherman Weissman (Yale), Kevin White (UChicago), and Peter Zandi (JHU). This work was supported by funding provided by Autism Science Foundation postdoctoral fellowships (to D.W. and J.-Y.A.) and a research award (to S.J.S.); Simons Foundation Autism Research Initiative (SFARI) grants 574598 (to S.J.S.), 402281 (to S.J.S. M.W.S. B.D. and K.R.), and 573206 (to M.E.T.); National Institute for Mental Health (NIMH) grants R01 MH109901 (to S.J.S. and M.W.S.), R01 MH110928 (to S.J.S. and M.W.S.), U01 MH103339 (to M.W.S.), R01 MH111662 (to S.J.S. and M.W.S.), U01 MH105575 (to M.W.S.), U01 MH106874 (to N.S.), P50 MH106934 (to N.S.), R01 MH109904 (to N.S.), R01 MH110926 (to N.S.), U01 MH116488 (to N.S.), R37 MH057881 (to B.D.), and R01 MH115957 (to M.E.T.); National Institute of Child Health and Human Development (NICHD) grants R24 HD000836 (to I.A.G.), R01 HD081256 (to M.E.T.), and R01 HD096326 (to M.E.T.); National Heart, Lung, and Blood Institute (NHLBI) grant K25HL121295 (to N.A.Z.); National Human Genome Research Institute (NHGRI) grants U01HG009080 (to N.A.Z.) and R01HG006399 (to N.A.Z.); National Cancer Institute (NCI) grant R01CA227237 (to N.A.Z.); National Institute of Dental and Craniofacial Research (NIDCR) grant R03DE025665 (to N.A.Z.); United States Department of Defense (DoD) grant W81XWH-16-2-0018 (to N.A.Z.); and National Research Foundation of Korea grant 2019M3E5D3073568 (to J.-Y.A.). The project that gave rise to these results also received the support of a fellowship from ?la Caixa? Foundation (ID 100010434 to G.S.). The fellowship code is LCF/BQ/PI19/11690010. We thank Thomas Lehner, Anjen? Addington, Geetha Senthil, and Alexander Arguello at the NIMH for supporting the PsychENCODE Consortium, the Yale Center for Genome Analysis for generating the RNA-seq data, GENEWIZ for generating the WGS data, and Sentieon for use of a computationally efficient implementation of GATK Haplotype Caller. Conceptualization, K.R. M.W.S. B.D. S.J.S. and N.S.; Methodology, D.M.W. S.P. J.C. J.-Y.A. H.A.-B. J.-L.T. K.A.A. D.R.O. I.A.G. K.R. M.W.S. B.D. S.J.S. and N.S.; Software, D.M.W. J.-Y.A. C.D. L.L. M.C.G. and S.J.S.; Validation, D.M.W. S.P. J.C. J.-Y.A. C.D. S.D. B.D. S.J.S. and N.S.; Formal Analysis, D.M.W. S.P. J.C. J.-Y.A. B.S. M.P. G.S. M.S.B. L.K. A.E.C. B.D. and S.J.S.; Investigation, D.M.W. S.P. J.C. J.-Y.A. B.S. B.D. S.J.S. and N.S.; Resources, S.P. J.C. Z.L. C.D. A.M.M.S, A.T.N.T. N.K. F.O.G. L.L. M.C.G. X.Z. H.A.-B. J.-L.T. K.A.A. D.R.O. I.A.G. M.E.T. S.J.S. and N.S.; Data Curation, D.M.W. S.P. J.C. C.D. L.L. M.C.G. X.Z. S.D. and S.J.S.; Statistical analysis, D.M.W. J.C. J.-Y.A. B.S. M.P. M.S.B. B.D. and S.J.S.; Writing ? Original Draft, D.M.W. S.P. J.C. J.-Y.A. B.S. B.D. S.J.S. and N.S.; Writing ? Review & Editing, D.M.W. S.P. J.C. J.-Y.A. B.S. M.P. Z.L. C.D. G.S. A.M.M.S. A.T.N.T. N.K. F.O.G. M.S.B. L.L. M.C.G. X.Z. S.D. L.K. A.E.C. J.D.B. H.A.-B. J.-L.T. K.A.A. D.R.O. I.A.G. N.A.Z. M.E.T. K.R. M.W.S. B.D. S.J.S. and N.S.; Visualization, D.M.W. S.P. J.C. J.-Y.A. B.S. S.J.S. and N.S.; Supervision, J.D.B. N.A.Z. M.E.T. K.R. M.W.S. B.D. S.J.S. and N.S.; Project Administration, D.M.W. S.P. S.J.S. and N.S.; Funding Acquisition, K.R. M.W.S. B.D. S.J.S. and N.S. The authors declare no competing interests. Publisher Copyright: © 2020 The Author(s)
PY - 2020/4/7
Y1 - 2020/4/7
N2 - Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development. Here we identify common variants that alter gene expression (expression quantitative trait loci [eQTLs]) constantly across development or predominantly during prenatal or postnatal stages. Both “constant” and “temporal-predominant” eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology.
AB - Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development. Here we identify common variants that alter gene expression (expression quantitative trait loci [eQTLs]) constantly across development or predominantly during prenatal or postnatal stages. Both “constant” and “temporal-predominant” eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology.
KW - BrainVar
KW - DLPFC
KW - LOC101926933 RP11-298I3.1 AL132780.1 ENSG00000257285
KW - PsychENCODE
KW - RHEBL1
KW - dorsolateral prefrontal cortex
KW - fetal transition
KW - mTOR
KW - prenatal eQTL
UR - http://www.scopus.com/inward/record.url?scp=85082762940&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2020.03.053
DO - 10.1016/j.celrep.2020.03.053
M3 - Article
C2 - 32268104
AN - SCOPUS:85082762940
SN - 2211-1247
VL - 31
JO - Cell Reports
JF - Cell Reports
IS - 1
M1 - 107489
ER -