Dataset Information

Single-Nuclei RNA Sequencing of 5 Regions of the Human Prenatal Brain Implicates Developing Neuron Populations in Genetic Risk for Schizophrenia.

ABSTRACT:

Background

While a variety of evidence supports a prenatal component in schizophrenia, there are few data regarding the cell populations involved. We sought to identify cells of the human prenatal brain mediating genetic risk for schizophrenia by integrating cell-specific gene expression measures generated through single-nuclei RNA sequencing with recent large-scale genome-wide association study (GWAS) and exome sequencing data for the condition.

Methods

Single-nuclei RNA sequencing was performed on 5 brain regions (frontal cortex, ganglionic eminence, hippocampus, thalamus, and cerebellum) from 3 fetuses from the second trimester of gestation. Enrichment of schizophrenia common variant genetic liability and rare damaging coding variation was assessed in relation to gene expression specificity within each identified cell population.

Results

Common risk variants were prominently enriched within genes with high expression specificity for developing neuron populations within the frontal cortex, ganglionic eminence, and hippocampus. Enrichments were largely independent of genes expressed in neuronal populations of the adult brain that have been implicated in schizophrenia through the same methods. Genes containing an excess of rare damaging variants in schizophrenia had higher expression specificity for developing glutamatergic neurons of the frontal cortex and hippocampus that were also enriched for common variant liability.

Conclusions

We found evidence for a distinct contribution of prenatal neuronal development to genetic risk for schizophrenia, involving specific populations of developing neurons within the second-trimester fetal brain. Our study significantly advances the understanding of the neurodevelopmental origins of schizophrenia and provides a resource with which to investigate the prenatal antecedents of other psychiatric and neurologic disorders.

SUBMITTER: Cameron D

PROVIDER: S-EPMC10804933 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Single-Nuclei RNA Sequencing of 5 Regions of the Human Prenatal Brain Implicates Developing Neuron Populations in Genetic Risk for Schizophrenia.

Cameron Darren D Mi Da D Vinh Ngoc-Nga NN Webber Caleb C Li Meng M Marín Oscar O O'Donovan Michael C MC Bray Nicholas J NJ

Biological psychiatry 20220715 2

<h4>Background</h4>While a variety of evidence supports a prenatal component in schizophrenia, there are few data regarding the cell populations involved. We sought to identify cells of the human prenatal brain mediating genetic risk for schizophrenia by integrating cell-specific gene expression measures generated through single-nuclei RNA sequencing with recent large-scale genome-wide association study (GWAS) and exome sequencing data for the condition.<h4>Methods</h4>Single-nuclei RNA sequenci ...[more]

PMID: 36150908

Similar Datasets

Project description:BackgroundSchizophrenia (SCZ) is a heterogeneous psychiatric disorder, with significant contribution from genetic factors particularly for chronic cases with negative symptoms and cognitive deficits. To date, Genome Wide Association Studies (GWAS) and exome sequencing have associated SCZ with a number of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs), but there is still missing heritability. Medium-sized structural variants (SVs) are difficult to detect using SNP arrays or second generation sequencing, and may account for part of the missing heritability of SCZ.Aims and objectivesTo identify SVs associated with severe chronic SCZ across the whole genome.Study design10 multiplex families with probands suffering from chronic SCZ with negative symptoms and cognitive deficits were recruited, with all their affected members demonstrating uni-lineal inheritance. Control subjects comprised one affected member from the affected lineage, and unaffected members from each paternal and maternal lineage.MethodsThird generation sequencing was applied to peripheral blood samples from 10 probands and 5 unaffected controls. Bioinformatic tools were used to identify SVs from the long sequencing reads, with confirmation of findings in probands by short-read Illumina sequencing, Sanger sequencing and visual manual validation with Integrated Genome Browser.ResultsIn the 10 probands, we identified and validated 88 SVs (mostly in introns and medium-sized), within 79 genes, which were absent in the 5 unaffected control subjects. These 79 genes were enriched in 20 biological pathways which were related to brain development, neuronal migration, neurogenesis, neuronal/synaptic function, learning/memory, and hearing. These identified SVs also showed evidence for enrichment of genes that are highly expressed in the adolescent striatum.ConclusionA substantial part of the missing heritability in SCZ may be explained by medium-sized SVs detectable only by third generation sequencing. We have identified a number of such SVs potentially conferring risk for SCZ, which implicate multiple brain-related genes and pathways. In addition to previously-identified pathways involved in SCZ such as neurodevelopment and neuronal/synaptic functioning, we also found novel evidence for enrichment in hearing-related pathways and genes expressed in the adolescent striatum.

Dataset Information

Single-Nuclei RNA Sequencing of 5 Regions of the Human Prenatal Brain Implicates Developing Neuron Populations in Genetic Risk for Schizophrenia.

Background

Methods

Results

Conclusions

Publications

Single-Nuclei RNA Sequencing of 5 Regions of the Human Prenatal Brain Implicates Developing Neuron Populations in Genetic Risk for Schizophrenia.

Similar Datasets

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