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

Ma, Liang; Semick, Stephen A.; Chen, Qiang; Li, Chao; Tao, Ran; Price, Amanda J.; Shin, Joo Heon; Jia, Yankai; Brandon, Nicholas J.; Cross, A.J.; Hyde, Thomas M.; Kleinman, Joel E.; Jaffe, Andrew E.; Weinberger, Daniel R.; Straub, Richard E.

doi:10.1038/s41380-018-0293-0

Cited by 41 publications

(37 citation statements)

References 39 publications

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“…To evaluate this possibility, we hybridized postmortem human DLPFC with probes targeting SLC17A7 (Opal690), GAD1 (Opal620), and SNX19 (sorting nexin 19, Opal570), a gene associated with genetic risk for schizophrenia 36 (Fig. S10).…”

Section: Dotdotdot Accommodates Smfish Data Acquired With Alternativementioning

confidence: 99%

dotdotdot: an automated approach to quantify multiplex single molecule fluorescent in situ hybridization (smFISH) images in complex tissues

Maynard

Tippani

Takahashi

et al. 2019

Preprint

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ABSTRACTMultiplex single-molecule fluorescent in situ hybridization (smFISH) is a powerful method for validating RNA sequencing and emerging spatial transcriptomic data, but quantification remains a computational challenge. We present a framework for generating and analyzing smFISH data in complex tissues while overcoming autofluorescence and increasing multiplexing capacity. We developed dotdotdot (https://github.com/LieberInstitute/dotdotdot) as a corresponding software package to quantify RNA transcripts in single nuclei and perform differential expression analysis. We first demonstrate robustness of our platform in single mouse neurons by quantifying differential expression of activity-regulated genes. We then quantify spatial gene expression in human dorsolateral prefrontal cortex (DLPFC) using spectral imaging and dotdotdot to mask lipofuscin autofluorescence. We lastly apply machine learning to predict cell types and perform downstream cell type-specific expression analysis. In summary, we provide experimental workflows, imaging acquisition and analytic strategies for quantification and biological interpretation of smFISH data in complex tissues.

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Section: Dotdotdot Accommodates Smfish Data Acquired With Alternativementioning

confidence: 99%

dotdotdot: an automated approach to quantify multiplex single molecule fluorescent in situ hybridization (smFISH) images in complex tissues

Maynard

Tippani

Takahashi

et al. 2019

Preprint

Self Cite

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“…Recently, skipping of exon 2 and exon 3 of AS3MT was identified to 1 contribute to SCZ risk using large postmortem brain cohorts (6). Using the same specimens, we 2 also successfully identified risk allele of SCZ SNPs are strongly associated with splicing junctions 3 between exon 8 and exon 10 of SNX19 (7). 4…”

Section: Introductionmentioning

confidence: 81%

“…generating new animal and cellular models for SCZ. The association of SNX19 splicing junction Exon_8.10 has been previously characterized in our prior work (7). Relative position of CYP2D6 SNPs and histone marker are indicated.…”

mentioning

confidence: 94%

“…To 16 illuminate our understanding of SCZ risk in splicing junction level, we systematically evaluated 17 the exon-exon junctions in the human brain. We found eight splicing junctions located within 18 In prior work, we have systematically characterized splice junctions between exon 8 and exon 10 1 in SNX19 (7). 2 3 To determine how SCZ GWAS relates to feature expression, we next analyzed the trends of the 4 associations.…”

mentioning

confidence: 99%

“…Our recent study has systematically evaluated SNX19 Exon_8.10 transcripts and their potential 23 susceptibility to SCZ (7). APOPT1 was demonstrated to be located in mitochondria matrix, and 1 involved in possessing an N-terminal mitochondrial targeting signal (28).…”

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confidence: 99%

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Variations and expression features of CYP2D6 contribute to schizophrenia risk

Ma¹,

Chetty

2019

Preprint

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1 Objective: Genome-wide association studies (GWAS) have successfully identified 145 loci 2 implicated in schizophrenia (SCZ). However, the underlying mechanisms remain largely 3 unknown. 4Methods: Here, we analyze 1,479 RNA-seq data from 13 postmortem brain regions in 5 combination with their genotype data and identify SNPs that are associated with expression 6 throughout the genome by dissecting expression features to genes (eGene) and exon-exon 7 junctions (eJunction). Then, we co-localize eGene and eJunction with SCZ GWAS using SMR and 8 mapping. Multiple ChIP-seq data and DNA methylation data generated from brain were used for 9 identifying the causative variants. Finally, we used a hypothesis-free (no SCZ risk loci considered) 10 enrichment analysis to determine implicated pathways. 11 Results:We identified 171 genes and eight splicing junctions located within four genes (SNX19, 12 ARL6IP4, APOPT1 and CYP2D6) that potentially contribute to SCZ susceptibility. Among the 13 genes, CYP2D6 is significantly associated with SCZ SNPs in both eGene and eJunction across the 14 13 brain regions. In-depth examination of the CYP2D6 region revealed that a non-synonymous 15 single nucleotide variant (SNV) rs16947 is strongly associated with a higher abundance of 16 CYP2D6 exon 3 skipping junctions. While we found rs133377 and two other SNPs in high linkage 17 disequilibrium (LD) with rs16947 (r 2 = 0.9539), histone acetylation analysis showed they are 18 located within active transcription start sites. Furthermore, our data-driven enrichment analysis 19 showed CYP2D6 is significantly involved in drug metabolism of tamoxifen, codeine and 20 citalopram. 21 Conclusions:Our study facilitates an understanding of the genetic architecture of SCZ and 22 provides new drug targets. 23

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Significance of an altered lncRNA landscape in schizophrenia and cognition: clues from a case–control association study

Mukhopadhyay

Deshpande

Bhatia

et al. 2023

Eur Arch Psychiatry Clin Neurosci

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

Cited by 41 publications

References 39 publications

dotdotdot: an automated approach to quantify multiplex single molecule fluorescent in situ hybridization (smFISH) images in complex tissues

dotdotdot: an automated approach to quantify multiplex single molecule fluorescent in situ hybridization (smFISH) images in complex tissues

Variations and expression features of CYP2D6 contribute to schizophrenia risk

Significance of an altered lncRNA landscape in schizophrenia and cognition: clues from a case–control association study

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