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rabindra.tharu.np@gmail.com
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Joint testing of rare variant burden scores using non-negative least squares
Gene-based burden tests are a popular and powerful approach for analysis of exome-wide association studies. These approaches combine sets of variants within a gene into a single burden score that is then tested for association. Typically, a range of burden scores are calculated and tested across a range of annotation classes and frequency bins. Correlation…
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rabindra.tharu.np@gmail.com
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Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs
Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies of genomic syndromes in both clinical and population cohorts, the mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion and 89 duplication carrier individuals among unrelated White British UK Biobank participants, we performed a phenome-wide association study (PheWAS) between the region’s…
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rabindra.tharu.np@gmail.com
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Calibration of variant effect predictors on genome-wide data masks heterogeneous performance across genes
In silico variant effect predictions are available for nearly all missense variants but played a minimal role in clinical variant classification because they were deemed to provide only supporting evidence. Recently, the ClinGen Sequence Variant Interpretation (SVI) Working Group updated recommendations for variant effect prediction use. By analyzing control pathogenic and benign variants across all…
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rabindra.tharu.np@gmail.com
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Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel
The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for…
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rabindra.tharu.np@gmail.com
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Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset
Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene…
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rabindra.tharu.np@gmail.com
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Omnibus proteome-wide association study identifies 43 risk genes for Alzheimer disease dementia
Transcriptome-wide association study (TWAS) tools have been applied to conduct proteome-wide association studies (PWASs) by integrating proteomics data with genome-wide association study (GWAS) summary data. The genetic effects of PWAS-identified significant genes are potentially mediated through genetically regulated protein abundance, thus informing the underlying disease mechanisms better than GWAS loci. However, existing TWAS/PWAS tools are…
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rabindra.tharu.np@gmail.com
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Long-read proteogenomics to connect disease-associated sQTLs to the protein isoform effectors of disease
A major fraction of loci identified by genome-wide association studies (GWASs) mediate alternative splicing, but mechanistic interpretation is hindered by the technical limitations of short-read RNA sequencing (RNA-seq), which cannot directly link splicing events to full-length protein isoforms. Long-read RNA-seq represents a powerful tool to characterize transcript isoforms, and recently, infer protein isoform existence. Here,…
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rabindra.tharu.np@gmail.com
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Benchmarking Mendelian randomization methods for causal inference using genome-wide association study summary statistics
Mendelian randomization (MR), which utilizes genetic variants as instrumental variables (IVs), has gained popularity as a method for causal inference between phenotypes using genetic data. While efforts have been made to relax IV assumptions and develop new methods for causal inference in the presence of invalid IVs due to confounding, the reliability of MR methods…
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rabindra.tharu.np@gmail.com
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Misexpression of inactive genes in whole blood is associated with nearby rare structural variants
Gene misexpression is the aberrant transcription of a gene in a context where it is usually inactive. Despite its known pathological consequences in specific rare diseases, we have a limited understanding of its wider prevalence and mechanisms in humans. To address this, we analyzed gene misexpression in 4,568 whole-blood bulk RNA sequencing samples from INTERVAL…
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rabindra.tharu.np@gmail.com
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Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome
The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare…
