Jordan Cahoon

All Publications

• Imputation accuracy across global human populations AMERICAN JOURNAL OF HUMAN GENETICS Cahoon, J. L., Rui, X., Tang, E., Simons, C., Langie, J., Chen, M., Lo, Y., Chiang, C. W. K. 2024; 111 (5): 979-989

  Abstract

  Genotype imputation is now fundamental for genome-wide association studies but lacks fairness due to the underrepresentation of references from non-European ancestries. The state-of-the-art imputation reference panel released by the Trans-Omics for Precision Medicine (TOPMed) initiative improved the imputation of admixed African-ancestry and Hispanic/Latino samples, but imputation for populations primarily residing outside of North America may still fall short in performance due to persisting underrepresentation. To illustrate this point, we imputed the genotypes of over 43,000 individuals across 123 populations around the world and identified numerous populations where imputation accuracy paled in comparison to that of European-ancestry populations. For instance, the mean imputation r-squared (Rsq) for variants with minor allele frequencies between 1% and 5% in Saudi Arabians (n = 1,061), Vietnamese (n = 1,264), Thai (n = 2,435), and Papua New Guineans (n = 776) were 0.79, 0.78, 0.76, and 0.62, respectively, compared to 0.90-0.93 for comparable European populations matched in sample size and SNP array content. Outside of Africa and Latin America, Rsq appeared to decrease as genetic distances to European-ancestry reference increased, as predicted. Using sequencing data as ground truth, we also showed that Rsq may over-estimate imputation accuracy for non-European populations more than European populations, suggesting further disparity in accuracy between populations. Using 1,496 sequenced individuals from Taiwan Biobank as a second reference panel to TOPMed, we also assessed a strategy to improve imputation for non-European populations with meta-imputation, but this design did not improve accuracy across frequency spectra. Taken together, our analyses suggest that we must ultimately strive to increase diversity and size to promote equity within genetics research.

  View details for DOI 10.1016/j.ajhg.2024.03.011

  View details for Web of Science ID 001273037500004

  View details for PubMedID 38604166

  View details for PubMedCentralID PMC11080279

• Inverted genomic regions between reference genome builds in humans impact imputation accuracy and decrease the power of association testing. HGG advances Sheng, X., Xia, L., Cahoon, J. L., Conti, D. V., Haiman, C. A., Kachuri, L., Chiang, C. W. 2023; 4 (1): 100159

  Abstract

  Over the last two decades, the human reference genome has undergone multiple updates as we complete a linear representation of our genome. Two versions of human references are currently used in the biomedical literature, GRCh37/hg19 and GRCh38. Conversions between these versions are critical for quality control, imputation, and association analysis. In the present study, we show that single-nucleotide variants (SNVs) in regions inverted between different builds of the reference genome are often mishandled bioinformatically. Depending on the array type, SNVs are found in approximately 2-5 Mb of the genome that are inverted between reference builds. Coordinate conversions of these variants are mishandled by both the TOPMed imputation server as well as routine in-house quality control pipelines, leading to underrecognized downstream analytical consequences. Specifically, we observe that undetected allelic conversion errors for palindromic (i.e., A/T or C/G) variants in these inverted regions would destabilize the local haplotype structure, leading to loss of imputation accuracy and power in association analyses. Though only a small proportion of the genome is affected, these regions include important disease susceptibility variants that would be affected. For example, the p value of a known locus associated with prostate cancer on chromosome 10 (chr10) would drop from 2.86 × 10-7 to 0.0011 in a case-control analysis of 20,286 Africans and African Americans (10,643 cases and 9,643 controls). We devise a straight-forward heuristic based on the popular tool, liftOver, that can easily detect and correct these variants in the inverted regions between genome builds to locally improve imputation accuracy.

  View details for DOI 10.1016/j.xhgg.2022.100159

  View details for PubMedID 36465187

  View details for PubMedCentralID PMC9709082

• Continuous Stress Monitoring for Healthcare Workers: Evaluating Generalizability Across Real-World Datasets Cahoon, J. L., Garcia, L. A., ACM ASSOC COMPUTING MACHINERY. 2023

  View details for DOI 10.1145/3584371.3612974

  View details for Web of Science ID 001143941200031

• PGD₂ and CRTH2 counteract Type 2 cytokine-elicited intestinal epithelial responses during helminth infection JOURNAL OF EXPERIMENTAL MEDICINE Oyesola, O. O., Shanahan, M. T., Kanke, M., Mooney, B. M., Webb, L. M., Smita, S., Matheson, M. K., Campioli, P., Pham, D., Fruh, S. P., McGinty, J. W., Churchill, M. J., Cahoon, J. L., Sundaravaradan, P., Flitter, B. A., Mouli, K., Nadjsombati, M. S., Kamynina, E., Peng, S. A., Cubitt, R. L., Gronert, K., Lord, J. D., Rauch, I., von Moltke, J., Sethupathy, P., Wojno, E. 2021; 218 (9)

  Abstract

  Type 2 inflammation is associated with epithelial cell responses, including goblet cell hyperplasia, that promote worm expulsion during intestinal helminth infection. How these epithelial responses are regulated remains incompletely understood. Here, we show that mice deficient in the prostaglandin D2 (PGD2) receptor CRTH2 and mice with CRTH2 deficiency only in nonhematopoietic cells exhibited enhanced worm clearance and intestinal goblet cell hyperplasia following infection with the helminth Nippostrongylus brasiliensis. Small intestinal stem, goblet, and tuft cells expressed CRTH2. CRTH2-deficient small intestinal organoids showed enhanced budding and terminal differentiation to the goblet cell lineage. During helminth infection or in organoids, PGD2 and CRTH2 down-regulated intestinal epithelial Il13ra1 expression and reversed Type 2 cytokine-mediated suppression of epithelial cell proliferation and promotion of goblet cell accumulation. These data show that the PGD2-CRTH2 pathway negatively regulates the Type 2 cytokine-driven epithelial program, revealing a mechanism that can temper the highly inflammatory effects of the anti-helminth response.

  View details for DOI 10.1084/jem.20202178

  View details for Web of Science ID 000701689900006

  View details for PubMedID 34283207

  View details for PubMedCentralID PMC8294949