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Article: Third-generation genome sequencing implicates medium-sized structural variants in chronic schizophrenia

TitleThird-generation genome sequencing implicates medium-sized structural variants in chronic schizophrenia
Authors
Keywordsbiological pathways
chronic and negative symptoms
intronic
multiplex families
schizophrenia
striatum
structural variants
third generation sequencing
Issue Date11-Jan-2023
PublisherFrontiers Media
Citation
Frontiers in Neuroscience, 2023, v. 16 How to Cite?
AbstractBackgroundSchizophrenia (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.
Persistent Identifierhttp://hdl.handle.net/10722/337606
ISSN
2023 SCImago Journal Rankings: 1.063
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLee, CC-
dc.contributor.authorYe, R-
dc.contributor.authorTubbs, JD-
dc.contributor.authorBaum, L-
dc.contributor.authorZhong, YX-
dc.contributor.authorLeung, SYJ-
dc.contributor.authorChan, SC-
dc.contributor.authorWu, KYK-
dc.contributor.authorCheng, PKJ-
dc.contributor.authorChow, LP-
dc.contributor.authorLeung, PWL-
dc.contributor.authorSham, PC-
dc.date.accessioned2024-03-11T10:22:28Z-
dc.date.available2024-03-11T10:22:28Z-
dc.date.issued2023-01-11-
dc.identifier.citationFrontiers in Neuroscience, 2023, v. 16-
dc.identifier.issn1662-4548-
dc.identifier.urihttp://hdl.handle.net/10722/337606-
dc.description.abstractBackgroundSchizophrenia (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.-
dc.languageeng-
dc.publisherFrontiers Media-
dc.relation.ispartofFrontiers in Neuroscience-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectbiological pathways-
dc.subjectchronic and negative symptoms-
dc.subjectintronic-
dc.subjectmultiplex families-
dc.subjectschizophrenia-
dc.subjectstriatum-
dc.subjectstructural variants-
dc.subjectthird generation sequencing-
dc.titleThird-generation genome sequencing implicates medium-sized structural variants in chronic schizophrenia-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3389/fnins.2022.1058359-
dc.identifier.pmid36711134-
dc.identifier.scopuseid_2-s2.0-85147028988-
dc.identifier.volume16-
dc.identifier.eissn1662-453X-
dc.identifier.isiWOS:000920109400001-
dc.publisher.placeLAUSANNE-
dc.identifier.issnl1662-453X-

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