title: Genome-wide identification of splicing QTLs in the human brain and their enrichment among schizophrenia-associated loci.
abstract: Detailed analyses of transcriptome have revealed complexity in regulation of alternative splicing (AS). These AS events often undergo modulation by genetic variants. Here we analyse RNA-sequencing data of prefrontal cortex from 206 individuals in combination with their genotypes and identify cis-acting splicing quantitative trait loci (sQTLs) throughout the genome. These sQTLs are enriched among exonic and H3K4me3-marked regions. Moreover, we observe significant enrichment of sQTLs among disease-associated loci identified by GWAS, especially in schizophrenia risk loci. Closer examination of each schizophrenia-associated loci revealed four regions (each encompasses NEK4, FXR1, SNAP91 or APOPT1), where the index SNP in GWAS is in strong linkage disequilibrium with sQTL SNP(s), suggesting dysregulation of AS as the underlying mechanism of the association signal. Our study provides an informative resource of sQTL SNPs in the human brain, which can facilitate understanding of the genetic architecture of complex brain disorders such as schizophrenia.
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.|Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takata
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Tadafumi
authors.identifier: 0000-0001-7856-3952
authors.initials: T
authors.lastname: Kato
mesh_terms: D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D022821:RNA Splice Sites; D012333:RNA, Messenger