Christopher Vittal

Integrating 730,947 exome sequences with clinical literature improves gene discovery

gnomAD v4 (730,947 exomes) brings LOFTEE-2 loss-of-function annotation (0.90 precision, strict mode), missense-aware constraint, and LLM-mined literature evidence combined with constraint to rank disease genes.

The Scalable Variant Call Representation: Enabling Genetic Analysis Beyond One Million Genomes

This paper introduces SVCR, a scalable variant call format that reduces file size and enables efficient analysis of large genetic datasets.

The landscape of regional missense mutational intolerance quantified from 730,947 exomes

The paper quantifies regional missense mutational intolerance using 730,947 exomes to identify constrained gene regions and improve variant interpretation.

A genome-wide mutational constraint map quantified from variation in 76,156 human genomes

Rare-variant depletion in 1kb windows of 76,156 gnomAD genomes, versus feature-adjusted mutation expectations, marks regulatory elements and outperforms seven alternative scores at flagging functional non-coding variants.

Systematic single-variant and gene-based association testing of thousands of phenotypes in 426,370 UK Biobank exomes

The paper performs single-variant and gene-based association analyses of 4,529 phenotypes using exome data from 426,370 UK Biobank individuals, finding associations linked to variant frequency and deleteriousness.

Evaluating potential drug targets through human loss-of-function genetic variation

The paper evaluates potential drug targets using loss-of-function genetic variants from gnomAD, highlighting the importance of deep curation and targeted recall studies for drug discovery.

The mutational constraint spectrum quantified from variation in 141,456 humans

From 125,748 exomes and 15,708 genomes, 443,769 high-confidence predicted loss-of-function variants yield LOEUF, a continuous gene intolerance score tracking mouse lethality, cell essentiality, and disease associations.

Transcript expression-aware annotation improves rare variant discovery and interpretation

The paper develops an expression-based annotation metric to improve rare variant interpretation by filtering false-positive loss-of-function variants and identifying pathogenic variants in highly expressed exons.

An open resource of structural variation for medical and population genetics

Short-read genome sequencing of 14,891 diverse genomes yields 433,371 structural variants (SVs) for gnomAD; loss-constrained genes also resist duplication, and clinical SV carrier rates are benchmarked.

Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinsons disease

The paper analyzes loss-of-function variants in LRRK2 across large genomic datasets to assess the safety of partial LRRK2 inhibition as a Parkinson's disease therapy.

Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals

The paper systematically studies uORF variants in 15,708 genomes, showing they are under strong negative selection and contribute to disease.

Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes

The paper analyzes multi-nucleotide variants (MNVs) in 125,748 exomes and 15,708 genomes, identifying their distribution, mutational origins, and functional implications.