An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease–related patterns

Jin, Bowen; Capra, John A.; Benchek, Penelope; Wheeler, Nicholas R.; Naj, Adam C; Hamilton‐Nelson, Kara L.; Farrell, John; Leung, Yuk Yee; Kunkle, Brian W.; Vardarajan, Badri N.; Schellenberg, Gerard D.; Mayeux, Richard; Wang, Li-San; Farrer, Lindsay A.; Pericak‐Vance, Margaret A.; Martin, Eden R.; Haines, Jonathan L.; Crawford, Dana C.; Bush, William S.

doi:10.1101/gr.276069.121

Cited by 5 publications

(4 citation statements)

References 26 publications

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“…The enlarged knowledge of protein structures can help us elucidate the molecular mechanisms of more variants. Leveraging protein structures from protein structure databases, three statistical methods - POINT [ 74 ], PSCAN [ 75 ], and POKEMON [ 76 ] - have been developed to characterize the association between rare missense variants and phenotypes by integrating 3D spatial distance of variants within protein structures.…”

Section: Future Directionsmentioning

confidence: 99%

Statistical methods for assessing the effects of de novo variants on birth defects

Xie,

Wu,

et al. 2024

Hum Genomics

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With the development of next-generation sequencing technology, de novo variants (DNVs) with deleterious effects can be identified and investigated for their effects on birth defects such as congenital heart disease (CHD). However, statistical power is still limited for such studies because of the small sample size due to the high cost of recruiting and sequencing samples and the low occurrence of DNVs. DNV analysis is further complicated by genetic heterogeneity across diseased individuals. Therefore, it is critical to jointly analyze DNVs with other types of genomic/biological information to improve statistical power to identify genes associated with birth defects. In this review, we discuss the general workflow, recent developments in statistical methods, and future directions for DNV analysis.

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Section: Future Directionsmentioning

confidence: 99%

Statistical methods for assessing the effects of de novo variants on birth defects

Xie,

Wu,

et al. 2024

Hum Genomics

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“…Rare-variant tests typically allow for the incorporation of variant weights, which can be derived using variant annotations such as allele frequencies or functional variant effect predictions (129,132,(136)(137)(138). The directionality of functional variant effect predictions can also be taken into account, which could enable, for example, the separate collapsing of variants predicted to increase or decrease expression at a specific locus.…”

Section: Functional Predictions In Rare-variant Association Studiesmentioning

confidence: 99%

Toward Identification of Functional Sequences and Variants in Noncoding DNA

Monti

Ohler

2023

Annu. Rev. Biomed. Data Sci.

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Understanding the noncoding part of the genome, which encodes gene regulation, is necessary to identify genetic mechanisms of disease and translate findings from genome-wide association studies into actionable results for treatments and personalized care. Here we provide an overview of the computational analysis of noncoding regions, starting from gene-regulatory mechanisms and their representation in data. Deep learning methods, when applied to these data, highlight important regulatory sequence elements and predict the functional effects of genetic variants. These and other algorithms are used to predict damaging sequence variants. Finally, we introduce rare-variant association tests that incorporate functional annotations and predictions in order to increase interpretability and statistical power. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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“…Assessments were performed according to the same methodology as Jin, et al (2022). The methods in brief: Protein structures that were both experimentally solved and those that could not be experimentally solved were predicted, and those structures were taken from the structures in the Protein Databank (PDB) [29], and from both Swiss Model and ModBase.…”

Section: Spatial Assessmentsmentioning

confidence: 99%

“…All variants that failed to meet one or more criteria were presumed putatively neutral and excluded from all downstream analyses. We also employed an orthogonal approach as per Jin et al 34 , to determine if there was a spatial relationship between variants and case-status. This method uses a structural-kernel-based variance component test to incorporate spatial proximity between rare variants when calculating the gene-based statistic.…”

Section: Gene-based Testingmentioning

confidence: 99%

Spatial Distribution of Missense Variants within Complement Proteins Associates with Age Related Macular Degeneration

Grunin,

Jong,

Palmer

et al. 2023

Preprint

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Purpose: Genetic variants in complement genes are associated with age-related macular degeneration (AMD). However, many rare variants have been identified in these genes, but have an unknown significance, and their impact on protein function and structure is still unknown. We set out to address this issue by evaluating the spatial placement and impact on protein structure of these variants by developing an analytical pipeline and applying it to the International AMD Genomics Consortium (IAMDGC) dataset (16,144 AMD cases, 17,832 controls). Methods: The IAMDGC dataset was imputed using the Haplotype Reference Consortium (HRC), leading to an improvement of over 30% more imputed variants, over the original 1000 Genomes imputation. Variants were extracted for the CFH, CFI, CFB, C9, and C3 genes, and filtered for missense variants in solved protein structures. We evaluated these variants as to their placement in the three-dimensional structure of the protein (i.e. spatial proximity in the protein), as well as AMD association. We applied several pipelines to a) calculate spatial proximity to known AMD variants versus gnomAD variants, b) assess a variants likelihood of causing protein destabilization via calculation of predicted free energy change (ddG) using Rosetta, and c) whole gene-based testing to test for statistical associations. Gene-based testing using seqMeta was performed using a) all variants b) variants near known AMD variants or c) with a ddG >|2|. Further, we applied a structural kernel adaptation of SKAT testing (POKEMON) to confirm the association of spatial distributions of missense variants to AMD. Finally, we used logistic regression on known AMD variants in CFI to identify variants leading to >50% reduction in protein expression from known AMD patient carriers of CFI variants compared to wild type (as determined by in vitro experiments) to determine the pipelines robustness in identifying AMD-relevant variants. These results were compared to functional impact scores, ie CADD values > 10, which indicate if a variant may have a large functional impact genomewide, to determine if our metrics have better discriminative power than existing variant assessment methods. Once our pipeline had been validated, we then performed a priori selection of variants using this pipeline methodology, and tested AMD patient cell lines that carried those selected variants from the EUGENDA cohort (n=34). We investigated complement pathway protein expression in vitro, looking at multiple components of the complement factor pathway in patient carriers of bioinformatically identified variants. Results: Multiple variants were found with a ddG>|2| in each complement gene investigated. Gene-based tests using known and novel missense variants identified significant associations of the C3, C9, CFB, and CFH genes with AMD risk after controlling for age and sex (P=3.22x10^-5;7.58x10^-6;2.1x10^-3;1.2x10^-31). ddG filtering and SKAT-O tests indicate that missense variants that are predicted to destabilize the protein, in both CFI and CFH, are associated with AMD (P=CFH:0.05, CFI:0.01, threshold of 0.05 significance). Our structural kernel approach identified spatial associations for AMD risk within the protein structures for C3, C9, CFB, CFH, and CFI at a nominal p-value of 0.05. Both ddG and CADD scores were predictive of reduced CFI protein expression, with ROC curve analyses indicating ddG is a better predictor (AUCs of 0.76 and 0.69, respectively). A priori in vitro analysis of variants in all complement factor genes indicated that several variants identified via bioinformatics programs PathProx/POKEMON in our pipeline via in vitro experiments caused significant change in complement protein expression (P=0.04) in actual patient carriers of those variants, via ELISA testing of proteins in the complement factor pathway, and were previously unknown to contribute to AMD pathogenesis. Conclusion: We demonstrate for the first time that missense variants in complement genes cluster together spatially and are associated with AMD case/control status. Using this method, we can identify CFI and CFH variants of previously unknown significance that are predicted to destabilize the proteins. These variants, both in and outside spatial clusters, can predict in-vitro tested CFI protein expression changes, and we hypothesize the same is true for CFH. A priori identification of variants that impact gene expression allow for classification for previously classified as VUS. Further investigation is needed to validate the models for additional variants and to be applied to all AMD-associated genes.

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An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease–related patterns

Cited by 5 publications

References 26 publications

Statistical methods for assessing the effects of de novo variants on birth defects

Statistical methods for assessing the effects of de novo variants on birth defects

Toward Identification of Functional Sequences and Variants in Noncoding DNA

Spatial Distribution of Missense Variants within Complement Proteins Associates with Age Related Macular Degeneration

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