Browsing by Author "Ober, Carole"

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    Chromosome 17q12-21 Variants Are Associated with Multiple Wheezing Phenotypes in Childhood
    (American Thoracic Society, 2021) Hallmark, Brian; Wegienka, Ganesa; Havstad, Suzanne; Billheimer, Dean; Ownby, Dennis; Mendonca, Eneida A.; Gress, Lisa; Stern, Debra A.; Biagini Myers, Jocelyn; Khurana Hershey, Gurjit K.; Hoepner, Lori; Miller, Rachel L.; Lemanske, Robert F.; Jackson, Daniel J.; Gold, Diane R.; O’Connor, George T.; Nicolae, Dan L.; Gern, James E.; Ober, Carole; Wright, Anne L.; Martinez, Fernando D.; ECHO-CREW; Pediatrics, School of Medicine
    Rationale: Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated with asthma, are also associated with childhood wheezing phenotypes remains poorly explored. Objectives: To determine whether wheezing phenotypes, defined by latent class analysis (LCA), are associated with nine 17q12-21 SNPs and if so, whether these relationships differ by race/ancestry. Methods: Data from seven U.S. birth cohorts (n = 3,786) from the CREW (Children’s Respiratory Research and Environment Workgroup) were harmonized to represent whether subjects wheezed in each year of life from birth until age 11 years. LCA was then performed to identify wheeze phenotypes. Genetic associations between SNPs and wheeze phenotypes were assessed separately in European American (EA) (n = 1,308) and, for the first time, in African American (AA) (n = 620) children. Measurements and Main Results: The LCA best supported four latent classes of wheeze: infrequent, transient, late-onset, and persistent. Odds of belonging to any of the three wheezing classes (vs. infrequent) increased with the risk alleles for multiple SNPs in EA children. Only one SNP, rs2305480, showed increased odds of belonging to any wheezing class in both AA and EA children. Conclusions: These results indicate that 17q12-21 is a “wheezing locus,” and this association may reflect an early life susceptibility to respiratory viruses common to all wheezing children. Which children will have their symptoms remit or reoccur during childhood may be independent of the influence of rs2305480.
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    EndoPRS: Incorporating Endophenotype Information to Improve Polygenic Risk Scores for Clinical Endpoints
    (medRxiv, 2024-05-24) Kharitonova, Elena V.; Sun, Quan; Ockerman, Frank; Chen, Brian; Zhou, Laura Y.; Cao, Hongyuan; Mathias, Rasika A.; Auer, Paul L.; Ober, Carole; Raffield, Laura M.; Reiner, Alexander P.; Cox, Nancy J.; Kelada, Samir; Tao, Ran; Li, Yun; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Polygenic risk score (PRS) prediction of complex diseases can be improved by leveraging related phenotypes. This has motivated the development of several multi-trait PRS methods that jointly model information from genetically correlated traits. However, these methods do not account for vertical pleiotropy between traits, in which one trait acts as a mediator for another. Here, we introduce endoPRS, a weighted lasso model that incorporates information from relevant endophenotypes to improve disease risk prediction without making assumptions about the genetic architecture underlying the endophenotype-disease relationship. Through extensive simulation analysis, we demonstrate the robustness of endoPRS in a variety of complex genetic frameworks. We also apply endoPRS to predict the risk of childhood onset asthma in UK Biobank by leveraging a paired GWAS of eosinophil count, a relevant endophenotype. We find that endoPRS significantly improves prediction compared to many existing PRS methods, including multi-trait PRS methods, MTAG and wMT-BLUP, which suggests advantages of endoPRS in real-life clinical settings.