Author Correction: Transcript expression-aware annotation improves rare variant interpretation

Cummings, Beryl B.; Team, Genome Aggregation Database Production; Karczewski, Konrad J.; Kosmicki, Jack A.; Seaby, Eleanor G.; Watts, Nicholas A.; Singer-Berk, Moriel; Mudge, Jonathan M.; Karjalainen, Juha; Satterstrom, F. Kyle; O’Donnell-Luria, Anne H.; Poterba, Timothy; Seed, Cotton; Solomonson, Matthew; Alföldi, Jessica; Daly, Mark J.; MacArthur, Daniel G.

doi:10.1038/s41586-020-03175-7

Cited by 21 publications

(44 citation statements)

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“…This suggests that the signal is not solely driven by the most pathogenic variants nor direct rare variant effects on splicing. These results extend the previous work, comparing different exons and showing accumulation of stop-gained variants on those with lower inclusion (Cummings et al 2020). Here, observe a similar pattern when comparing different individuals within a given exon, consistent with the hypothesis that the penetrance of coding alleles is reduced when they fall on more lowly included exons.…”

Section: Resultssupporting

confidence: 91%

“…Alternative splicing is responsible for the great diversity of isoform structures observed across human tissues and cell types (Keren et al 2010). With regard to coding variant interpretation, exons with lower expression have been shown to be less likely to harbor pathogenic variants, while ubiquitously included exons can be prioritized for gene disrupting rare variants (Cummings et al 2020). Autistic individuals with variants on the same exons have been shown to have remarkably similar disease phenotypes, putatively due to the variants having similar effects on gene dosage or function, a notable finding given the extreme heterogeneity of the condition (Chiang et al 2021).…”

Section: Introductionmentioning

confidence: 99%

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Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Einson

Glinos

Boerwinkle

et al. 2023

Preprint

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Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Einson

Glinos

Boerwinkle

et al. 2023

Preprint

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“…UTMOST 18 modestly improves average imputation r 2 across tissues over PrediXcan by 36.8% 18 . Moreover, genes associated with Mendelian diseases are likely depleted for common cis-eQTLs 40,[51][52][53][54][55] . Future studies could potentially incorporate methods that use rare eQTLs 53 , trans-eQTLs, and epigenetic information 56 to predict gene expression.…”

Section: Discussionmentioning

confidence: 99%

Investigating the role of commoncis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders

Wigdor

Samocha

Eberhardt

et al. 2023

Preprint

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Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi-cis-expression quantitative trait loci (cis-eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6,987 probands from the Deciphering Developmental Disorders (DDD) study and 9,720 controls, and found one gene,RAB2A, that passed multiple testing correction (p = 6.7×10-7). We then investigated whethercis-eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1,700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7×10-3). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that commoncis-eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.

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“…To move from population-level to individual genetic risk mechanisms, we next used our atlas to reinterpret de novo, noncoding genetic variations reported to be associated with ASD ( 81 – 83 ) and intellectual disability/developmental disorders (ID/DD) ( 83 ). We reasoned that some previously identified noncoding variants may carry newfound transcriptional activity based on the >27MB of new annotations.…”

Section: Main Textmentioning

confidence: 99%

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

Patowary

Zhang

Jops

et al. 2023

Preprint

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Human brain development is under tight molecular genetic control and the recent advent of single-cell genomics has revolutionized our ability to elucidate the diverse underlying cell-types and states. Although RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders, previous work has not systematically investigated the role of cell-type-specific splicing or transcript-isoform diversity during human brain development. Here, we leverage single molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone (GZ) and cortical plate (CP) regions of the developing human neocortex at tissue and single-cell resolution. We identify 214,516 unique isoforms, corresponding to 22,391 genes. Remarkably, we find that 72.6% of these are novel and together with >7,000 novel-spliced exons expands the proteome by 92,422 proteoforms. We uncover myriad novel isoform switches during cortical neurogenesis, implicating previously-uncharacterized RNA-binding protein-mediated and other regulatory mechanisms in cellular identity and disease. Early-stage excitatory neurons exhibit the greatest isoform diversity and isoform-based single-cell clustering identifies previously uncharacterized cell states. Leveraging this resource, we re-prioritize thousands of rare de novo risk variants associated with neurodevelopmental disorders (NDDs) and reveal that risk genes are strongly associated with the number of unique isoforms observed per gene. Altogether, this work uncovers a substantial contribution of transcript-isoform diversity in cellular identity in the developing neocortex, elucidates novel genetic risk mechanisms for neurodevelopmental and neuropsychiatric disorders, and provides a comprehensive isoform-centric gene annotation for the developing human brain.

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Author Correction: Transcript expression-aware annotation improves rare variant interpretation

Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03175-7

Cited by 21 publications

References 0 publications

Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Investigating the role of commoncis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

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