Ruowang Li1,2, Rui Duan2, Rachel L Kember3,4,5, Daniel J Rader3,6, Scott M Damrauer4,7, Jason H Moore1,2, Yong Chen1,2. 1. Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 2. Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 3. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 4. Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA. 5. Regeneron Genetics Center, Tarrytown, New York, USA. 6. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 7. Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract
OBJECTIVE: Pleiotropy, where 1 genetic locus affects multiple phenotypes, can offer significant insights in understanding the complex genotype-phenotype relationship. Although individual genotype-phenotype associations have been thoroughly explored, seemingly unrelated phenotypes can be connected genetically through common pleiotropic loci or genes. However, current analyses of pleiotropy have been challenged by both methodologic limitations and a lack of available suitable data sources. MATERIALS AND METHODS: In this study, we propose to utilize a new regression framework, reduced rank regression, to simultaneously analyze multiple phenotypes and genotypes to detect pleiotropic effects. We used a large-scale biobank linked electronic health record data from the Penn Medicine BioBank to select 5 cardiovascular diseases (hypertension, cardiac dysrhythmias, ischemic heart disease, congestive heart failure, and heart valve disorders) and 5 mental disorders (mood disorders; anxiety, phobic and dissociative disorders; alcohol-related disorders; neurological disorders; and delirium dementia) to validate our framework. RESULTS: Compared with existing methods, reduced rank regression showed a higher power to distinguish known associated single-nucleotide polymorphisms from random single-nucleotide polymorphisms. In addition, genome-wide gene-based investigation of pleiotropy showed that reduced rank regression was able to identify candidate genetic variants with novel pleiotropic effects compared to existing methods. CONCLUSION: The proposed regression framework offers a new approach to account for the phenotype and genotype correlations when identifying pleiotropic effects. By jointly modeling multiple phenotypes and genotypes together, the method has the potential to distinguish confounding from causal genotype and phenotype associations.
OBJECTIVE: Pleiotropy, where 1 genetic locus affects multiple phenotypes, can offer significant insights in understanding the complex genotype-phenotype relationship. Although individual genotype-phenotype associations have been thoroughly explored, seemingly unrelated phenotypes can be connected genetically through common pleiotropic loci or genes. However, current analyses of pleiotropy have been challenged by both methodologic limitations and a lack of available suitable data sources. MATERIALS AND METHODS: In this study, we propose to utilize a new regression framework, reduced rank regression, to simultaneously analyze multiple phenotypes and genotypes to detect pleiotropic effects. We used a large-scale biobank linked electronic health record data from the Penn Medicine BioBank to select 5 cardiovascular diseases (hypertension, cardiac dysrhythmias, ischemic heart disease, congestive heart failure, and heart valve disorders) and 5 mental disorders (mood disorders; anxiety, phobic and dissociative disorders; alcohol-related disorders; neurological disorders; and delirium dementia) to validate our framework. RESULTS: Compared with existing methods, reduced rank regression showed a higher power to distinguish known associated single-nucleotide polymorphisms from random single-nucleotide polymorphisms. In addition, genome-wide gene-based investigation of pleiotropy showed that reduced rank regression was able to identify candidate genetic variants with novel pleiotropic effects compared to existing methods. CONCLUSION: The proposed regression framework offers a new approach to account for the phenotype and genotype correlations when identifying pleiotropic effects. By jointly modeling multiple phenotypes and genotypes together, the method has the potential to distinguish confounding from causal genotype and phenotype associations.
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