Polygenic risk for triglyceride levels in the presence of a high impact rare variant
Abstract Background Elevated triglyceride (TG) levels are a heritable and modifiable risk factor for cardiovascular disease and have well-established associations with common genetic variation captured in a polygenic risk score (PRS). In young adulthood, the 22q11.2 microdeletion conveys a 2-fold in...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | BMC Medical Genomics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12920-023-01717-2 |
| _version_ | 1797451158512467968 |
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| author | Shengjie Ying Tracy Heung Bhooma Thiruvahindrapuram Worrawat Engchuan Yue Yin Christina Blagojevic Zhaolei Zhang Robert A. Hegele Ryan K. C. Yuen Anne S. Bassett |
| author_facet | Shengjie Ying Tracy Heung Bhooma Thiruvahindrapuram Worrawat Engchuan Yue Yin Christina Blagojevic Zhaolei Zhang Robert A. Hegele Ryan K. C. Yuen Anne S. Bassett |
| author_sort | Shengjie Ying |
| collection | DOAJ |
| description | Abstract Background Elevated triglyceride (TG) levels are a heritable and modifiable risk factor for cardiovascular disease and have well-established associations with common genetic variation captured in a polygenic risk score (PRS). In young adulthood, the 22q11.2 microdeletion conveys a 2-fold increased risk for mild-moderate hypertriglyceridemia. This study aimed to assess the role of the TG-PRS in individuals with this elevated baseline risk for mild-moderate hypertriglyceridemia. Methods We studied a deeply phenotyped cohort of adults (n = 157, median age 34 years) with a 22q11.2 microdeletion and available genome sequencing, lipid level, and other clinical data. The association between a previously developed TG-PRS and TG levels was assessed using a multivariable regression model adjusting for effects of sex, BMI, and other covariates. We also constructed receiver operating characteristic (ROC) curves using logistic regression models to assess the ability of TG-PRS and significant clinical variables to predict mild-moderate hypertriglyceridemia status. Results The TG-PRS was a significant predictor of TG-levels (p = 1.52E-04), along with male sex and BMI, in a multivariable model (pmodel = 7.26E-05). The effect of TG-PRS appeared to be slightly stronger in individuals with obesity (BMI ≥ 30) (beta = 0.4617) than without (beta = 0.1778), in a model unadjusted for other covariates (p-interaction = 0.045). Among ROC curves constructed, the inclusion of TG-PRS, sex, and BMI as predictor variables produced the greatest area under the curve (0.749) for classifying those with mild-moderate hypertriglyceridemia, achieving an optimal sensitivity and specificity of 0.746 and 0.707, respectively. Conclusions These results demonstrate that in addition to significant effects of sex and BMI, genome-wide common variation captured in a PRS also contributes to the variable expression of the 22q11.2 microdeletion with respect to elevated TG levels. |
| first_indexed | 2024-03-09T14:50:47Z |
| format | Article |
| id | doaj.art-e3b86bf5315244c5ade858fc4967c998 |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-03-09T14:50:47Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-e3b86bf5315244c5ade858fc4967c9982023-11-26T14:30:05ZengBMCBMC Medical Genomics1755-87942023-11-0116111110.1186/s12920-023-01717-2Polygenic risk for triglyceride levels in the presence of a high impact rare variantShengjie Ying0Tracy Heung1Bhooma Thiruvahindrapuram2Worrawat Engchuan3Yue Yin4Christina Blagojevic5Zhaolei Zhang6Robert A. Hegele7Ryan K. C. Yuen8Anne S. Bassett9Institute of Medical Science, University of TorontoClinical Genetics Research Program, Centre for Addiction and Mental HealthThe Centre for Applied Genomics, The Hospital for Sick ChildrenThe Centre for Applied Genomics, The Hospital for Sick ChildrenThe Centre for Applied Genomics, The Hospital for Sick ChildrenClinical Genetics Research Program, Centre for Addiction and Mental HealthDepartment of Molecular Genetics, University of TorontoSchulich School of Medicine and Dentistry, Western UniversityThe Centre for Applied Genomics, The Hospital for Sick ChildrenInstitute of Medical Science, University of TorontoAbstract Background Elevated triglyceride (TG) levels are a heritable and modifiable risk factor for cardiovascular disease and have well-established associations with common genetic variation captured in a polygenic risk score (PRS). In young adulthood, the 22q11.2 microdeletion conveys a 2-fold increased risk for mild-moderate hypertriglyceridemia. This study aimed to assess the role of the TG-PRS in individuals with this elevated baseline risk for mild-moderate hypertriglyceridemia. Methods We studied a deeply phenotyped cohort of adults (n = 157, median age 34 years) with a 22q11.2 microdeletion and available genome sequencing, lipid level, and other clinical data. The association between a previously developed TG-PRS and TG levels was assessed using a multivariable regression model adjusting for effects of sex, BMI, and other covariates. We also constructed receiver operating characteristic (ROC) curves using logistic regression models to assess the ability of TG-PRS and significant clinical variables to predict mild-moderate hypertriglyceridemia status. Results The TG-PRS was a significant predictor of TG-levels (p = 1.52E-04), along with male sex and BMI, in a multivariable model (pmodel = 7.26E-05). The effect of TG-PRS appeared to be slightly stronger in individuals with obesity (BMI ≥ 30) (beta = 0.4617) than without (beta = 0.1778), in a model unadjusted for other covariates (p-interaction = 0.045). Among ROC curves constructed, the inclusion of TG-PRS, sex, and BMI as predictor variables produced the greatest area under the curve (0.749) for classifying those with mild-moderate hypertriglyceridemia, achieving an optimal sensitivity and specificity of 0.746 and 0.707, respectively. Conclusions These results demonstrate that in addition to significant effects of sex and BMI, genome-wide common variation captured in a PRS also contributes to the variable expression of the 22q11.2 microdeletion with respect to elevated TG levels.https://doi.org/10.1186/s12920-023-01717-2TriglycerideLipidPolygenic risk score22q11.2 microdeletionGenome sequencing |
| spellingShingle | Shengjie Ying Tracy Heung Bhooma Thiruvahindrapuram Worrawat Engchuan Yue Yin Christina Blagojevic Zhaolei Zhang Robert A. Hegele Ryan K. C. Yuen Anne S. Bassett Polygenic risk for triglyceride levels in the presence of a high impact rare variant BMC Medical Genomics Triglyceride Lipid Polygenic risk score 22q11.2 microdeletion Genome sequencing |
| title | Polygenic risk for triglyceride levels in the presence of a high impact rare variant |
| title_full | Polygenic risk for triglyceride levels in the presence of a high impact rare variant |
| title_fullStr | Polygenic risk for triglyceride levels in the presence of a high impact rare variant |
| title_full_unstemmed | Polygenic risk for triglyceride levels in the presence of a high impact rare variant |
| title_short | Polygenic risk for triglyceride levels in the presence of a high impact rare variant |
| title_sort | polygenic risk for triglyceride levels in the presence of a high impact rare variant |
| topic | Triglyceride Lipid Polygenic risk score 22q11.2 microdeletion Genome sequencing |
| url | https://doi.org/10.1186/s12920-023-01717-2 |
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