TY - JOUR
T1 - Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain
AU - PsychENCODE Consortium
AU - Wen, Cindy
AU - Margolis, Michael
AU - Dai, Rujia
AU - Zhang, Pan
AU - Przytycki, Pawel F.
AU - Vo, Daniel D.
AU - Bhattacharya, Arjun
AU - Matoba, Nana
AU - Tang, Miao
AU - Jiao, Chuan
AU - Kim, Minsoo
AU - Tsai, Ellen
AU - Hoh, Celine
AU - Aygün, Nil
AU - Walker, Rebecca L.
AU - Chatzinakos, Christos
AU - Clarke, Declan
AU - Pratt, Henry
AU - Peters, Mette A.
AU - Gerstein, Mark
AU - Daskalakis, Nikolaos P.
AU - Weng, Zhiping
AU - Jaffe, Andrew E.
AU - Kleinman, Joel E.
AU - Hyde, Thomas M.
AU - Weinberger, Daniel R.
AU - Bray, Nicholas J.
AU - Sestan, Nenad
AU - Geschwind, Daniel H.
AU - Roeder, Kathryn
AU - Gusev, Alexander
AU - Pasaniuc, Bogdan
AU - Stein, Jason L.
AU - Love, Michael I.
AU - Pollard, Katherine S.
AU - Liu, Chunyu
AU - Gandal, Michael J.
N1 - Publisher Copyright:
© 2024 the authors, some rights reserved.
PY - 2024/5/24
Y1 - 2024/5/24
N2 - Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.
AB - Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.
UR - https://www.scopus.com/pages/publications/85194127808
UR - https://www.scopus.com/pages/publications/85194127808#tab=citedBy
U2 - 10.1126/science.adh0829
DO - 10.1126/science.adh0829
M3 - Article
C2 - 38781368
AN - SCOPUS:85194127808
SN - 0036-8075
VL - 384
JO - Science
JF - Science
IS - 6698
M1 - eadh0829
ER -