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Analysis of neuropsychiatric risk gene isoforms in the brain

ABSTRACT: Neuropsychiatric disorders are highly complex conditions and the risk of developing a disorder has been tied to hundreds of genomic variants that alter the expression and/or products (isoforms) made by risk genes. However, how these genes contribute to disease risk and onset through altered expression and RNA splicing is not well understood. Here we show our current understanding of gene isoforms is far from complete and reveal the precise splicing profiles of neuropsychiatric disorder risk genes. Combining our new bioinformatic pipeline IsoLamp with nanopore long-read amplicon sequencing, we deeply profiled the RNA isoform repertoire of 31 high-confidence neuropsychiatric disorder risk genes in human brain. We show most risk genes are more complex than previously reported, identifying 443 novel isoforms and 28 novel exons, including isoforms which alter protein domains, and genes such as ATG13 and GATAD2A where most expression was from previously undiscovered isoforms. The greatest isoform diversity was present in the schizophrenia risk gene ITIH4. Mass spectrometry of brain protein isolates confirmed translation of a novel exon skipping event in ITIH4, suggesting a new regulatory mechanism for this gene in brain

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Benjamin Parker

LAB HEAD: Benjamin Parker

PROVIDER: PXD063836 | Pride | 2025-07-25

REPOSITORIES: pride

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			Action	DRS
	230927_Lumos_BP-7099_Ric_trypsin_1.raw	Raw
	230927_Lumos_BP-7099_Ric_trypsin_2.raw	Raw
	230927_Lumos_BP-7099_Ric_trypsin_3.raw	Raw
	230927_Lumos_BP-7099_Ric_trypsin_GPF1.raw	Raw
	230927_Lumos_BP-7099_Ric_trypsin_GPF2.raw	Raw

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Project description:The molecular basis of complex neuropsychiatric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizophrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann's area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18-67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes during the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. Keywords: postmortem human brain collection Supplementary files: Gene expression measures in Matrix1379Normalized.txt include all data from the 1379 probes on the arrays, and are NOT adjusted for PMI, brain pH, and RIN, and are NOT averaged over multiple probes within genes. Raw data are located in Raw_1241842_gene_probe_profile.txt. We have used custom DNA microarrays to investigate gene expression in the normal human brain. Expression was measured in Brodmann's area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18-67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse.

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Analysis of neuropsychiatric risk gene isoforms in the brain

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