Polygenic risk for triglyceride levels in the presence of a high impact rare variant

Shengjie Ying; Tracy Heung; Bhooma Thiruvahindrapuram; Worrawat Engchuan; Yue Yin; Christina Blagojevic; Zhaolei Zhang; Robert A Hegele; Ryan K C Yuen; Anne S Bassett

doi:10.1186/s12920-023-01717-2

Polygenic risk for triglyceride levels in the presence of a high impact rare variant

BMC Med Genomics. 2023 Nov 8;16(1):281. doi: 10.1186/s12920-023-01717-2.

Authors

Shengjie Ying^{1

2

3}, Tracy Heung^{3

4}, Bhooma Thiruvahindrapuram⁵, Worrawat Engchuan⁵, Yue Yin⁵, Christina Blagojevic³, Zhaolei Zhang^{6

7

8}, Robert A Hegele², Ryan K C Yuen^{5

6}, Anne S Bassett^{9

10

11

12

13}

Affiliations

¹ Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
² Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
³ Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁴ The Dalglish Family 22Q Clinic, University Health Network, Toronto, ON, Canada.
⁵ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁷ Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
⁸ Department of Computer Science, University of Toronto, Toronto, ON, Canada.
⁹ Institute of Medical Science, University of Toronto, Toronto, ON, Canada. anne.bassett@utoronto.ca.
¹⁰ Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON, Canada. anne.bassett@utoronto.ca.
¹¹ The Dalglish Family 22Q Clinic, University Health Network, Toronto, ON, Canada. anne.bassett@utoronto.ca.
¹² Department of Psychiatry, University of Toronto, Toronto, ON, Canada. anne.bassett@utoronto.ca.
¹³ Toronto General Hospital Research Institute and Campbell Family Mental Health Research Institute, Toronto, ON, Canada. anne.bassett@utoronto.ca.

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 (p_model = 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.

Keywords: 22q11.2 microdeletion; Genome sequencing; Lipid; Polygenic risk score; Triglyceride.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Cardiovascular Diseases*
Genome-Wide Association Study
Humans
Hypertriglyceridemia* / genetics
Male
Obesity
Risk Factors
Triglycerides
Young Adult

Substances

Triglycerides

Abstract

Publication types

MeSH terms

Substances

Grants and funding