Exome-wide evaluation of rare coding variants using electronic health records identifies new gene–phenotype associations

Park, Joseph; Lucas, Anastasia; Zhang, Mengjie; Chaudhary, Kumardeep; Cho, Judy H.; Nadkarni, Girish N.; Dobbyn, Amanda; Chittoor, Geetha; Josyula, Navya Shilpa; Katz, Nathan; Breeyear, Joseph H.; Ahmadmehrabi, Shadi; Drivas, Theodore G.; Chavali, Venkata R M; Fasolino, Maria; Sawada, Hisashi; Daugherty, Alan; Liu, Yanming; Zhang, Chen; Bradford, Yuki; Weaver, JoEllen; Verma, Anurag; Judy, Renae; Kember, Rachel; Overton, John D.; Reid, Jeffrey G.; Ferreira, Manuel; Li, Alexander H.; Baras, Aris; LeMaire, Scott A.; Shen, Ying H.; Naji, Ali; Kaestner, Klaus H.; Vahedi, Golnaz; Edwards, Todd L.; Chen, Jinbo; Damrauer, Scott M.; Justice, Anne E.; Do, Ron; Ritchie, Marylyn D.; Rader, Daniel J.

doi:10.1038/s41591-020-1133-8

Cited by 52 publications

(51 citation statements)

References 64 publications

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“…Gene-burden PheWAS applied to large healthcare-based biobanks has the potential to elucidate the medical consequences of gene variants on the human disease phenome. 5 A logical first step is to perform PheWAS focused only on predicted loss-of-function (pLOF) variants, which has the advantage of interrogating the largest effect sizes that a gene burden may have on associated phenotypes, but could lead to lack of power due to their infrequency. In aggregating pLOF variants in MYBPC3 and MYH7 for gene burden PheWAS in PMBB, only the MYBPC3 pLOF gene burden was associated with HCM, while the MYH7 pLOF gene burden was associated with other cardiac phenotypes and not HCM.…”

Section: Discussionmentioning

confidence: 99%

“…We used an additive genetic model to aggregate variants into gene burdens as previously described. 5 PheWAS analyses were performed separately by African and European genetic ancestry and then combined with inverse variance weighted meta-analysis.…”

Section: Phenome-wide Association Studiesmentioning

confidence: 99%

“…4 We have previously shown that gene-burden PheWAS applied to large healthcare populations has the potential to uncover novel consequences of rare coding variants in the human disease phenome. 5 One approach to gene-burden PheWAS is to focus only on predicted loss-offunction (pLOF) variants, but this could lead to lack of power due to their infrequency.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank

Park

Packard

Levin

et al. 2021

Preprint

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'Genome-first' approaches to analyzing rare variants can reveal new insights into human biology and disease. Because pathogenic variants are often rare, new discovery requires aggregating rare coding variants into 'gene burdens' for sufficient power. However, a major challenge is deciding which variants to include in gene burden tests. Pathogenic variants in MYBPC3 and MYH7 are well-known causes of hypertrophic cardiomyopathy (HCM), and focusing on these 'positive control' genes in a genome-first approach could help inform variant selection methods and gene burdening strategies for other genes and diseases. Integrating exome sequences with electronic health records among 41,759 participants in the Penn Medicine BioBank, we evaluated the performance of aggregating predicted loss-of-function (pLOF) and/or predicted deleterious missense (pDM) variants in MYBPC3 and MYH7 for gene burden phenome-wide association studies (PheWAS). The approach to grouping rare variants for these two genes produced very different results: pLOFs but not pDM variants in MYBPC3 were strongly associated with HCM, whereas the opposite was true for MYH7. Detailed review of clinical charts revealed that only 38.5% of patients with HCM diagnoses carrying an HCM-associated variant in MYBPC3 or MYH7 had a clinical genetic test result. Additionally, 26.7% of MYBPC3 pLOF carriers without HCM diagnoses had clear evidence of left atrial enlargement and/or septal/LV hypertrophy on echocardiography. Our study shows the importance of evaluating both pLOF and pDM variants for gene burden testing in future studies to uncover novel gene-disease relationships and identify new pathogenic loss-of-function variants across the human genome through genome-first analyses of healthcare-based populations.

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Section: Discussionmentioning

confidence: 99%

Section: Phenome-wide Association Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank

Park

Packard

Levin

et al. 2021

Preprint

Self Cite

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“…83 Such tests can be used to detect pharmacogenetic effects of rare variants in sequencing and exome data and have been shown to be able to detect the influence of deleterious variants in CYP2D6 on ADRs related to opioid use. 84 Phenome-wide association studies (PheWAS) have grown in interest as a method of identifying the effect of individual variants across a broad range of phenotypes. 85 PheWAS, much like GWAS, perform independent statistical tests analyzing the association between genotype and phenotype.…”

Section: Beyond Gwasmentioning

confidence: 99%

“…GWAS may not detect associations between independent rare variants unless the effect size is extremely large, but tests that aggregate the effects of rare or deleterious variants in a region or gene can be used to detect an effect 83 . Such tests can be used to detect PGx effects of rare variants in sequencing and exome data and have been shown to be able to detect the influence of deleterious variants in CYP2D6 on ADRs related to opioid use 84 …”

Section: Future Perspectivesmentioning

confidence: 99%

Genomewide Association Studies in Pharmacogenomics

McInnes

Yee

Pershad

et al. 2021

Clin Pharma and Therapeutics

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The increasing availability of genotype data linked with information about drug-response phenotypes has enabled genome-wide association studies (GWAS) that uncover genetic determinants of drug response. GWAS have discovered associations between genetic variants and both drug efficacy and adverse drug reactions. Despite these successes, the design of GWAS in pharmacogenomics faces unique challenges. In this review we analyze the last decade of GWAS in pharmacogenomics. We review trends in publications over time, including the drugs and drug classes studied and the clinical phenotypes used. Several data sharing consortia have contributed substantially to the PGx GWAS literature. We anticipate increased focus on biobanks and highlight phenotypes that would best enable future pharmacogenomics discoveries.

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Bidirectional Risk Modulator and Modifier Variant of Dilated and Hypertrophic Cardiomyopathy in BAG3

Park,

Levin,

Zhang

et al. 2024

JAMA Cardiol

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ImportanceThe genetic factors that modulate the reduced penetrance and variable expressivity of heritable dilated cardiomyopathy (DCM) are largely unknown. BAG3 genetic variants have been implicated in both DCM and hypertrophic cardiomyopathy (HCM), nominating BAG3 as a gene that harbors potential modifier variants in DCM.ObjectiveTo interrogate the clinical traits and diseases associated with BAG3 coding variation.Design, Setting, and ParticipantsThis was a cross-sectional study in the Penn Medicine BioBank (PMBB) enrolling patients of the University of Pennsylvania Health System’s clinical practice sites from 2014 to 2023. Whole-exome sequencing (WES) was linked to electronic health record (EHR) data to associate BAG3 coding variants with EHR phenotypes. This was a health care population-based study including individuals of European and African genetic ancestry in the PMBB with WES linked to EHR phenotypes, with replication studies in BioVU, UK Biobank, MyCode, and DCM Precision Medicine Study.ExposuresCarrier status for BAG3 coding variants.Main Outcomes and MeasuresAssociation of BAG3 coding variation with clinical diagnoses, echocardiographic traits, and longitudinal outcomes.ResultsIn PMBB (n = 43 731; median [IQR] age, 65 [50-76] years; 21 907 female [50.1%]), among 30 324 European and 11 198 African individuals, the common C151R variant was associated with decreased risk for DCM (odds ratio [OR], 0.85; 95% CI, 0.78-0.92) and simultaneous increased risk for HCM (OR, 1.59; 95% CI, 1.25-2.02), which was confirmed in the replication cohorts. C151R carriers exhibited improved longitudinal outcomes compared with noncarriers as assessed by age at death (hazard ratio [HR], 0.85; 95% CI, 0.74-0.96; median [IQR] age, 71.8 [63.1-80.7] in carriers and 70.3 [61.6-79.2] in noncarriers) and heart transplant (HR, 0.81; 95% CI, 0.66-0.99; median [IQR] age, 56.7 [46.1-63.1] in carriers and 55.6 [45.2-62.9] in noncarriers). C151R was associated with reduced risk of DCM (OR, 0.42; 95% CI, 0.24-0.74) and heart failure (OR, 0.27; 95% CI, 0.14-0.50) among individuals harboring truncating TTN variants in exons with high cardiac expression (n = 358).Conclusions and RelevanceBAG3 C151R was identified as a bidirectional modulator of risk along the DCM-HCM spectrum, as well as an important genetic modifier variant in TTN-mediated DCM. This work expands on the understanding of the etiology and penetrance of DCM, suggesting that BAG3 C151R is an important genetic modifier variant contributing to the variable expressivity of DCM, warranting further exploration of its mechanisms and of genetic modifiers in DCM more broadly.

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Exome-wide evaluation of rare coding variants using electronic health records identifies new gene–phenotype associations

Cited by 52 publications

References 64 publications

A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank

A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank

Genomewide Association Studies in Pharmacogenomics

Bidirectional Risk Modulator and Modifier Variant of Dilated and Hypertrophic Cardiomyopathy in BAG3

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