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.

Berlin Institute of Health at Charité Universitätsmedizin Berlin Berlin Germany

Bioinformatics Institute Agency for Science Technology and Research 30 Biopolis Street 07 01 Matrix Singapore 138671 Singapore; Rare Care Centre Perth Children's Hospital Nedlands WA 6009 Australia; SingHealth Duke NUS Institute of Precision Medicine 5 Hospital Drive Level 9 Singapore 169609 Singapore

Center for Genomic Medicine Massachusetts General Hospital Boston MA USA; Division of Genetics and Genomics Boston Children's Hospital Boston MA USA; Program in Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge MA USA

Centre of Cardiovascular Surgery and Transplantation Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Clinic for Immunology and Rheumatology Hanover Medical School Hanover Germany; Center for Chronic Immunodeficiency University Hospital Freiburg Satellite Center of RESiST Cluster of Excellence 2155 Hanover Medical School Hanover Germany

Department of Biomedical Informatics University of Colorado Anschutz Medical Campus Aurora CO 80045 USA

Department of Genetics University of North Carolina Chapel Hill Chapel Hill NC USA

Department of Genetics University of North Carolina Chapel Hill Chapel Hill NC USA; Department of Biostatistics University of North Carolina Chapel Hill Chapel Hill NC USA

Department of Human Genetics Donders Institute for Brain Cognition and Behaviour Radboud University Medical Center P O Box 9101 6500 HB Nijmegen the Netherlands

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital in Motol Prague Czech Republic

Department of Ophthalmology University Clinic Marburg Campus Fulda Fulda Germany

Department of Pediatrics Division of Genetic Medicine University of Washington 1959 NE Pacific Street Box 357371 Seattle WA 98195 USA

Department of Pediatrics Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

Department of Pediatrics Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany; German Center for Child and Adolescent Health Partner Site Leipzig Dresden Dresden Germany

Deutsches Herzzentrum der Charité Berlin Germany

Division of Environmental Genomics and Systems Biology Lawrence Berkeley National Laboratory 1 Cyclotron Road Berkeley CA 94720 USA

Institute of Medical and Human Genetics Charité Universitätsmedizin Berlin Berlin Germany

North West Thames Regional Genetics Service Northwick Park and St Mark's Hospitals London UK

The Jackson Laboratory for Genomic Medicine 10 Discovery Drive Farmington CT 06032 USA

The Jackson Laboratory for Genomic Medicine 10 Discovery Drive Farmington CT 06032 USA; Berlin Institute of Health at Charité Universitätsmedizin Berlin Berlin Germany; ELLIS the European Laboratory for Learning and Intelligent Systems Tübingen Germany

William Harvey Research Institute Faculty of Medicine and Dentistry Queen Mary University of London Charterhouse Square London EC1M 6BQ UK

medRxiv. 2025 Mar 06:2025.03.05.25323315. doi: 10.1101/2025.03.05.25323315. PubMed

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