Schizophrenia risk variants influence multiple classes of transcripts of sorting nexin 19 (SNX19).

Autor: Ma L; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA., Semick SA; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA., Chen Q; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA., Li C; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA., Tao R; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA., Price AJ; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA.; McKusick-Nathans Institute of Genetic Medicine, Baltimore, MD, 21205, USA., Shin JH; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA., Jia Y; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA., Brandon NJ; AstraZeneca Neuroscience, IMED Biotech Unit, AstraZeneca R&D, Boston, MA, 02451, USA., Cross AJ; AstraZeneca Neuroscience, IMED Biotech Unit, AstraZeneca R&D, Boston, MA, 02451, USA., Hyde TM; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Kleinman JE; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Jaffe AE; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA.; Department of Mental Health, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA.; Department of Biostatistics, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA., Weinberger DR; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA.; McKusick-Nathans Institute of Genetic Medicine, Baltimore, MD, 21205, USA.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Straub RE; Lieber Institute for Brain Development, Baltimore, MD, 21205, USA. richard.straub@libd.org.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2020 Apr; Vol. 25 (4), pp. 831-843. Date of Electronic Publication: 2019 Jan 11.
DOI: 10.1038/s41380-018-0293-0
Abstrakt: Genome-wide association studies (GWAS) have identified many genomic loci associated with risk for schizophrenia, but unambiguous identification of the relationship between disease-associated variants and specific genes, and in particular their effect on risk conferring transcripts, has proven difficult. To better understand the specific molecular mechanism(s) at the schizophrenia locus in 11q25, we undertook cis expression quantitative trait loci (cis-eQTL) mapping for this 2 megabase genomic region using postmortem human brain samples. To comprehensively assess the effects of genetic risk upon local expression, we evaluated multiple transcript features: genes, exons, and exon-exon junctions in multiple brain regions-dorsolateral prefrontal cortex (DLPFC), hippocampus, and caudate. Genetic risk variants strongly associated with expression of SNX19 transcript features that tag multiple rare classes of SNX19 transcripts, whereas they only weakly affected expression of an exon-exon junction that tags the majority of abundant transcripts. The most prominent class of SNX19 risk-associated transcripts is predicted to be overexpressed, defined by an exon-exon splice junction between exons 8 and 10 (junc8.10) and that is predicted to encode proteins that lack the characteristic nexin C terminal domain. Risk alleles were also associated with either increased or decreased expression of multiple additional classes of transcripts. With RACE, molecular cloning, and long read sequencing, we found a number of novel SNX19 transcripts that further define the set of potential etiological transcripts. We explored epigenetic regulation of SNX19 expression and found that DNA methylation at CpG sites near the primary transcription start site and within exon 2 partially mediate the effects of risk variants on risk-associated expression. ATAC sequencing revealed that some of the most strongly risk-associated SNPs are located within a region of open chromatin, suggesting a nearby regulatory element is involved. These findings indicate a potentially complex molecular etiology, in which risk alleles for schizophrenia generate epigenetic alterations and dysregulation of multiple classes of SNX19 transcripts.
Databáze: MEDLINE
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