Polygenic risk scores of endo-phenotypes identify the effect of genetic background in congenital heart disease

Sarah J. Spendlove; Leroy Bondhus; Gentian Lluri; Jae Hoon Sul; Valerie A. Arboleda

HGG Advances (Jul 2022)

Polygenic risk scores of endo-phenotypes identify the effect of genetic background in congenital heart disease

Sarah J. Spendlove,
Leroy Bondhus,
Gentian Lluri,
Jae Hoon Sul,
Valerie A. Arboleda

Affiliations

Sarah J. Spendlove: Interdepartmental Bioinformatics Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Leroy Bondhus: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Gentian Lluri: Ahmanson/UCLA Adult Congenital Heart Disease Center, Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Jae Hoon Sul: Interdepartmental Bioinformatics Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Valerie A. Arboleda: Interdepartmental Bioinformatics Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Corresponding author

Journal volume & issue: Vol. 3, no. 3
p. 100112

Abstract

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Congenital heart disease (CHD) is a rare structural defect that occurs in ∼1% of live births. Studies on CHD genetic architecture have identified pathogenic single-gene mutations in less than 30% of cases. Single-gene mutations often show incomplete penetrance and variable expressivity. Therefore, we hypothesize that genetic background may play a role in modulating disease expression. Polygenic risk scores (PRSs) aggregate effects of common genetic variants to investigate whether, cumulatively, these variants are associated with disease penetrance or severity. However, the major limitations in this field have been in generating sufficient sample sizes for these studies. Here we used CHD-phenotype matched genome-wide association study (GWAS) summary statistics from the UK Biobank (UKBB) as our base study and whole-genome sequencing data from the CHD cohort (n1 = 711 trios, n2 = 362 European trios) of the Gabriella Miller Kids First dataset as our target study to develop PRSs for CHD. PRSs estimated using a GWAS for heart valve problems and heart murmur explain 2.5% of the variance in case-control status of CHD (all SNVs, p = 7.90 × 10−3; fetal cardiac SNVs, p = 8.00 × 10−3) and 1.8% of the variance in severity of CHD (fetal cardiac SNVs, p = 6.20 × 10−3; all SNVs, p = 0.015). These results show that common variants captured in CHD phenotype-matched GWASs have a modest but significant contribution to phenotypic expression of CHD. Further exploration of the cumulative effect of common variants is necessary for understanding the complex genetic etiology of CHD and other rare diseases.

Published in HGG Advances

ISSN: 2666-2477 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics
Website: https://www.cell.com/hgg-advances/home

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