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Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium

Authors
Min-Zhi Jiang,Sheila M Gaynor
Xihao Li,Eric Van Buren,Adrienne Stilp,Erin Buth,Fei Fei Wang,Regina Manansala,Stephanie M Gogarten,Zilin Li,Linda M Polfus,Shabnam Salimi,Joshua C Bis,Nathan Pankratz,Lisa R Yanek,Peter Durda,Russell P Tracy,Stephen S Rich,Jerome I Rotter,Braxton D Mitchell,Joshua P Lewis,Bruce M Psaty,Katherine A Pratte,Edwin K Silverman,Robert C Kaplan,Christy Avery,Kari North,Rasika A Mathias,Nauder Faraday,Honghuang Lin,Biqi Wang,April P Carson,Arnita F Norwood,Richard A Gibbs,Charles Kooperberg,Jessica Lundin,Ulrike Peters,Josee Dupuis,Lifang Hou,Myriam Fornage,Emelia J Benjamin,Alexander P Reiner,Russell P Bowler,Xihong Lin,Paul L Auer,Laura M Raffield,NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,TOPMed Inflammation Working Group,Sheila Gaynor,Eric Buren,Fei Wang,Stephanie Gogarten,Linda Polfus,Joshua Bis,Lisa Yanek,Russell Tracy,Stephen Rich,Jerome Rotter,Braxton Mitchell,Joshua Lewis,Bruce Psaty,Katherine Pratte,Edwin Silverman,Robert Kaplan,Rasika Mathias,April Carson,Arnita Norwood,Richard Gibbs,Josée Dupuis,Emelia Benjamin,Alexander Reiner,Russell Bowler,Paul Auer,Feifei Wang
+72 authors
,Laura Raffield
Published
Jan 1, 2023
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Abstract

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits -- E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin -- that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were statistically distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

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