Evaluating drug targets through human loss-of-function genetic variation
Naturally occurring human genetic variants that are predicted to inactivate protein-coding
genes provide an in vivo model of human gene inactivation that complements knockout …
genes provide an in vivo model of human gene inactivation that complements knockout …
Identification of cis-suppression of human disease mutations by comparative genomics
Patterns of amino acid conservation have served as a tool for understanding protein
evolution. The same principles have also found broad application in human genomics …
evolution. The same principles have also found broad application in human genomics …
The mutational constraint spectrum quantified from variation in 141,456 humans
Genetic variants that inactivate protein-coding genes are a powerful source of information
about the phenotypic consequences of gene disruption: genes that are crucial for the …
about the phenotypic consequences of gene disruption: genes that are crucial for the …
From target discovery to clinical drug development with human genetics
The substantial investments in human genetics and genomics made over the past three
decades were anticipated to result in many innovative therapies. Here we investigate the …
decades were anticipated to result in many innovative therapies. Here we investigate the …
Genetic associations of protein-coding variants in human disease
Genome-wide association studies (GWAS) have identified thousands of genetic variants
linked to the risk of human disease. However, GWAS have so far remained largely …
linked to the risk of human disease. However, GWAS have so far remained largely …
The support of human genetic evidence for approved drug indications
Over a quarter of drugs that enter clinical development fail because they are ineffective.
Growing insight into genes that influence human disease may affect how drug targets and …
Growing insight into genes that influence human disease may affect how drug targets and …
The landscape of tolerated genetic variation in humans and primates
H Gao, T Hamp, J Ede, JG Schraiber, J McRae… - Science, 2023 - science.org
Personalized genome sequencing has revealed millions of genetic differences between
individuals, but our understanding of their clinical relevance remains largely incomplete. To …
individuals, but our understanding of their clinical relevance remains largely incomplete. To …
Protein-altering variants at copy number-variable regions influence diverse human phenotypes
MLA Hujoel, RE Handsaker, MA Sherman… - Nature Genetics, 2024 - nature.com
Copy number variants (CNVs) are among the largest genetic variants, yet CNVs have not
been effectively ascertained in most genetic association studies. Here we ascertained …
been effectively ascertained in most genetic association studies. Here we ascertained …
Using human genetics to improve safety assessment of therapeutics
Human genetics research has discovered thousands of proteins associated with complex
and rare diseases. Genome-wide association studies (GWAS) and studies of Mendelian …
and rare diseases. Genome-wide association studies (GWAS) and studies of Mendelian …
Validating therapeutic targets through human genetics
RM Plenge, EM Scolnick, D Altshuler - Nature reviews Drug discovery, 2013 - nature.com
More than 90% of the compounds that enter clinical trials fail to demonstrate sufficient safety
and efficacy to gain regulatory approval. Most of this failure is due to the limited predictive …
and efficacy to gain regulatory approval. Most of this failure is due to the limited predictive …