Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain.
Cindy WenMichael MargolisRujia DaiPan ZhangPawel F PrzytyckiDaniel D VoArjun BhattacharyaNana MatobaMiao TangChuan JiaoMinsoo KimEllen TsaiCeline HohNil AygünRebecca L WalkerChristos ChatzinakosDeclan ClarkeHenry E Prattnull nullMette A PetersMark B GersteinNikolaos P DaskalakisNishigandha PhalkeAndrew E JaffeJoel E KleinmanThomas M HydeDaniel R WeinbergerNicholas J BrayNenad SestanDaniel H GeschwindKathryn RoederAlexander GusevBogdan PasaniucJason L SteinMichael I LoveKatherine S PollardYanling LiuMichael J Gandalnull nullPublished in: Science (New York, N.Y.) (2024)
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.
Keyphrases
- genome wide
- dna methylation
- genome wide association
- single cell
- gene expression
- genome wide identification
- copy number
- autism spectrum disorder
- transcription factor
- genome wide association study
- high resolution
- endothelial cells
- rna seq
- resting state
- cerebral ischemia
- genome wide analysis
- intellectual disability
- preterm birth
- pregnant women
- induced pluripotent stem cells
- gestational age
- high density
- brain injury
- network analysis