Dataset Information

Ultrarare Missense Variants Implicated in Utah Pedigrees Multiply Affected With Schizophrenia.

ABSTRACT:

Background

Recent work from the Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) consortium showed significant enrichment of ultrarare variants in schizophrenia cases. Family-based studies offer a unique opportunity to evaluate rare variants because risk in multiplex pedigrees is more likely to be influenced by the same collection of variants than an unrelated cohort.

Methods

Here, we examine whole genome sequencing data from 35 individuals across 6 pedigrees multiply affected by schizophrenia. We applied a rigorous filtering pipeline to search for classes of protein-coding variants that cosegregated with disease status, and we examined these for evidence of enrichment in the SCHEMA dataset. Additionally, we applied a family-based consensus approach to call copy number variants and screen against a list of schizophrenia-associated risk variants.

Results

We identified deleterious missense variants in 3 genes (ATP2B2, SLC25A28, and GSK3A) that cosegregated with disease in 3 of the pedigrees. In the SCHEMA, the gene ATP2B2 shows highly suggestive evidence for deleterious missense variants in schizophrenia cases (p = .000072). ATP2B2 is involved in intracellular calcium homeostasis, expressed in multiple brain tissue types, and predicted to be intolerant to loss-of-function and missense variants.

Conclusions

We have identified genes that are likely to increase schizophrenia risk in 3 of the 6 pedigrees examined, the strongest evidence being for a gene involved in calcium homeostasis. Further work is required to examine other classes of variants that may be contributing to disease burden.

SUBMITTER: Ormond C

PROVIDER: S-EPMC10593875 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

Ultrarare Missense Variants Implicated in Utah Pedigrees Multiply Affected With Schizophrenia.

Ormond Cathal C Ryan Niamh M NM Heron Elizabeth A EA Gill Michael M Byerley William W Corvin Aiden A

Biological psychiatry global open science 20230216 4

<h4>Background</h4>Recent work from the Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) consortium showed significant enrichment of ultrarare variants in schizophrenia cases. Family-based studies offer a unique opportunity to evaluate rare variants because risk in multiplex pedigrees is more likely to be influenced by the same collection of variants than an unrelated cohort.<h4>Methods</h4>Here, we examine whole genome sequencing data from 35 individuals across 6 pedigrees multiply affecte ...[more]

PMID: 37881554

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Project description:ImportanceImpaired cognitive function in schizophrenia is associated with poor functional outcomes, but the role of rare coding variants is unclear.ObjectiveTo determine whether ultrarare constrained variants (URCVs) are associated with cognition in patients with schizophrenia.Design, setting, and participantsLinear regression was used to perform a within-case genetic association study of URCVs and current cognition and premorbid cognitive ability. A multivariable linear regression analysis of the outcomes associated with URCVs, schizophrenia polygenic risk score, polygenic risk score for intelligence and schizophrenia associated copy number variants on cognitive ability was performed. Exome sequencing data from 802 participants with schizophrenia were assessed for current cognition using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery and for estimated premorbid IQ using the National Adult Reading Test. Individuals were recruited from clinical and voluntary mental health services in the UK. Those with a diagnosis of intellectual disability or a neurological disorder known to affect cognition were excluded. Data collection occurred between 2007 and 2015. Data were analyzed between April 2020 and March 2022.Main outcomes and measuresAssociation between URCVs, current cognition, and current cognition adjusted for premorbid IQ.ResultsOf the 802 participants, 499 (62%) were men and 303 (38%) were women; mean (SD) age at interview was 43.36 (11.87) years. Ultrarare constrained variants (n = 400) were associated with lower current cognition scores (β = -0.18; SE = 0.07; P = .005). In the univariable analysis, premorbid IQ was associated with URCVs (β = -0.12; SE = 0.05; P = .02) and partly attenuated the association with current cognition (β = -0.09; SE = 0.05; P = .08). Multivariable analysis showed that measured genetic factors combined accounted for 6.2% of variance in current cognition, 10.3% of variance in premorbid IQ, and supported outcomes of URCVs associated with current cognition independent of premorbid IQ (β = -0.10; SE = 0.05; P = .03).Conclusions and relevanceThe findings of this study suggest that URCVs contribute to variance in cognitive function in schizophrenia, with partly independent associations before and after onset of the disorder. Although the estimated effect sizes were small, future studies may show that the effect sizes will be greater with better annotation of pathogenic variants. Genomic data may contribute to identifying those at particularly high risk of cognitive impairment in whom early remedial or preventive measures can be implemented.

Project description:BackgroundAutism Spectrum Disorders (ASD) are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS) which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability.MethodsWe present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC) methods to perform multilocus linkage analysis on large extended pedigrees.ResultsWhen analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD) = 2.91], 15q13.3 (HLOD = 3.64), and 13q12.3 (HLOD = 2.23). Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77). Additional positive quantitative results were seen on chromosomes 7, 9, and 19.ConclusionsThe SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis. In addition, we replicated a previous SRS peak in an independent sample. These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD. Finally, analyses of SRS scores revealed linkage peaks overlapping with evidence from other studies of neuropsychiatric diseases. The information available from the SRS itself may, therefore, reveal locations for autism susceptibility genes that would not otherwise be detected.

Dataset Information

Ultrarare Missense Variants Implicated in Utah Pedigrees Multiply Affected With Schizophrenia.

Background

Methods

Results

Conclusions

Publications

Ultrarare Missense Variants Implicated in Utah Pedigrees Multiply Affected With Schizophrenia.

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