PXD060711

PXD060711 is an original dataset announced via ProteomeXchange.

Title	A causal coding variant regulating alternative splicing of DOC2A at 16p.11.2 GWAS locus influences susceptibility to schizophrenia
Description	Genome-wide association studies (GWASs) have reported numerous genetic variations associated with schizophrenia, but knowledge regarding relevant molecular mechanisms is limited. Many genes undergo sophisticated alternative splicing in the brain, and aberrations of this process may contribute to the pathogenesis of schizophrenia. To examine modulated alternative splicing by genetic risk variant of schizophrenia, we performed genome-wide screening to identify schizophrenia risk single nucleotide polymorphisms that were associated with mRNA expression of alternative splicing junctions, especially previously unannotated junctions. Among the 14,465 schizophrenia risk SNPs, 17,107 splicing QTLs (sQTLs) for previously unannotated splicing junctions were identified in two independent brain RNA-Seq datasets (BrainSeq and CommonMind Consortium). Functional predictions using the deep neural network SpliceAI found 7 likely causal risk SNPs, among which a synonymous SNP rs3935873 in DOC2A at 16p11.2 GWAS locus showed the highest score and was significantly associated with elevated mRNA expression of a previously uncharacterized alternatively spliced DOC2AMutant isoform. In vitro minigene assays confirmed the selective regulatory effect of rs3935873 on the expression of DOC2AMutant rather than the wild-type DOC2AFull, suggesting its putatively causal role in the splicing of DOC2A. The SNP rs3935873 was significantly associated with hippocampal volume, and overexpressing DOC2AMutant in the hippocampus lead to multiple schizophrenia-like behavioral phenotypes, including aberrant prepulse inhibition (PPI), which are distinct from the mice overexpressing DOC2AFull. Both DOC2AMutant and DOC2AFull overexpression led to increased number of synapses, whereas DOC2AMutant reduced synaptic vesicle densities and postsynaptic density (PSD) width. Mechanistically, DOC2AMutant had distinct three-dimensional structure compared with DOC2AFull, and specifically-bound proteins were involved in the “regulation of actin cytoskeleton” and “Hippo signaling pathways”. Taken together, this study provides a splicing mechanism for the prominent 16p11.2 locus schizophrenia association, suggesting that sQTL analyses with previously uncharacterized isoforms could provide novel insights into the molecular mechanisms underlying GWAS associations.
HostingRepository	iProX
AnnounceDate	2025-02-12
AnnouncementXML	Submission_2025-02-12_00:48:11.052.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Miao Li
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-12 00:47:25	ID requested
⏵ 1	2025-02-12 00:48:11	announced

Dataset with its publication pending

submitter keyword: Schizophrenia, GWAS, DOC2A, Alternative splicing, Causal variant

Ming Li
contact affiliation	Kunming Institute of Zoology Chinese Academy of Sciences
contact email	limingkiz@mail.kiz.ac.cn
lab head
Miao Li
contact affiliation	Kunming Institute of Zoology Chinese Academy of Sciences
contact email	limiao1@mail.kiz.ac.cn
dataset submitter

iProX dataset URI