GA4GH phenopacket-driven characterization of genotype-phenotype correlations in Mendelian disorders
Comprehensively characterizing genotype-phenotype correlations (GPCs) in Mendelian disease would create new opportunities for improving clinical management and understanding disease biology. However, heterogeneous approaches to data sharing, reuse, and analysis have hindered progress in the field. We developed Genotype-Phenotype Statistical Evaluation of Associations (GPSEA), a software package that leverages the Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema to represent case-level clinical and genetic data about individuals. GPSEA applies an independent filtering strategy to boost statistical power to detect categorical GPCs represented by Human Phenotype Ontology terms. GPSEA additionally enables visualization and analysis of continuous phenotypes, clinical severity scores, and survival data such as age of onset of disease or clinical manifestations. We applied GPSEA to 85 cohorts with 6,179 previously published individuals with variants in one of 81 genes associated with 122 Mendelian diseases and identified 253 significant GPCs, with 48 cohorts having at least one statistically significant GPC. These results highlight the power of standardized representations of clinical data for scalable discovery of GPCs in Mendelian disease.
Authors
- Pilar Cacheiro (ORCID: https://orcid.org/0000-0002-6335-8208)
- Chris Mungall (ORCID: https://orcid.org/0000-0002-6601-2165)
- David Zocche (ORCID: https://orcid.org/0000-0003-1390-0334)
- Alexander Mordhorst
- Damian Smedley (ORCID: https://orcid.org/0000-0002-5836-9850)
- Tudor Groza (ORCID: https://orcid.org/0000-0003-2267-8333)
- Markus S. Ladewig (ORCID: https://orcid.org/0000-0002-6601-4486)
- Bert de Vries (ORCID: https://orcid.org/0000-0003-0839-174X)
- Timmy Strauß (ORCID: https://orcid.org/0000-0001-9969-9517)
- Michael Duyzend (ORCID: https://orcid.org/0000-0002-3941-6447)
- Sylvia Thun (ORCID: https://orcid.org/0000-0002-3346-6806)
- Angela Marcello
- Melissa Haendel (ORCID: https://orcid.org/0000-0001-9114-8737)
- Jessica X. Chong (ORCID: https://orcid.org/0000-0002-1616-2448)
- Evan Connelly (ORCID: https://orcid.org/0009-0001-4998-8617)
- Lauren Rekerle (ORCID: https://orcid.org/0000-0003-2598-6622)
- Viktor Bílý (ORCID: https://orcid.org/0000-0002-1252-4659)
- Justin Reese (ORCID: https://orcid.org/0000-0002-2170-2250)
- Leonardo Chimirri (ORCID: https://orcid.org/0000-0002-6912-8518)
- Ondřej Vladyka (ORCID: https://orcid.org/0009-0000-1737-4234)
- Filip Rehburg (ORCID: https://orcid.org/0009-0007-0457-5724)
- Peter Hansen (ORCID: https://orcid.org/0000-0001-5535-2845)
- Adam S.L. Graefe
- T. Freiberger
- Catharina Schuetz
- Peter N. Robinson
- Petra Gehle
- Michael I. Love
- Andrés Caballero-Oteyza
- Daniel Danis
- Julius O.B. Jacobsen
- Adam Klocperk
- Alexander J.M. Dingemans
- Monica C. Munoz-Torres
Institutions
- Broad Institute (US)
- Seattle Pacific University (US)
- University of North Carolina at Chapel Hill (US)
- Boston Children's Hospital (US)
- Radboud University Nijmegen (NL)
- Lawrence Berkeley National Laboratory (US)
- Charles University (CZ)
- Masaryk University (CZ)
- Radboud University Medical Center (NL)
- Medizinische Hochschule Hannover (DE)
- University Hospital in Motol (CZ)
- Singapore Institute for Clinical Sciences (SG)
- Deutsches Herzzentrum der Charité (DE)
- Jackson Laboratory (US)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- William Harvey Research Institute (GB)
- St Mark's Hospital (GB)
- University Hospital Carl Gustav Carus (DE)
- University of Colorado Anschutz Medical Campus (US)
- Technische Universität Dresden (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- The American Journal of Human Genetics
- Published
- 2025-12-23
- DOI
- https://doi.org/10.1016/j.ajhg.2025.12.001
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00