Publications


Professor of Pediatrics (Endocrinology) and of Genetics

Publications

  • Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes. Nature genetics Huerta-Chagoya, A., Schroeder, P., Mandla, R., Li, J., Morris, L., Vora, M., Alkanaq, A., Nagy, D., Szczerbinski, L., Madsen, J. G., Bonas-Guarch, S., Mollandin, F., Cole, J. B., Porneala, B., Westerman, K., Li, J. H., Pollin, T. I., Florez, J. C., Gloyn, A. L., Carey, D. J., Cebola, I., Mirshahi, U. L., Manning, A. K., Leong, A., Udler, M., Mercader, J. M. 2024

    Abstract

    Type 2 diabetes (T2D) genome-wide association studies (GWASs) often overlook rare variants as a result of previous imputation panels' limitations and scarce whole-genome sequencing (WGS) data. We used TOPMed imputation and WGS to conduct the largest T2D GWAS meta-analysis involving 51,256 cases of T2D and 370,487 controls, targeting variants with a minor allele frequency as low as 5*10-5. We identified 12 new variants, including a rare African/African American-enriched enhancer variant near the LEP gene (rs147287548), associated with fourfold increased T2D risk. We also identified a rare missense variant in HNF4A (p.Arg114Trp), associated with eightfold increased T2D risk, previously reported in maturity-onset diabetes of the young with reduced penetrance, but observed here in a T2D GWAS. We further leveraged these data to analyze 1,634 ClinVar variants in 22 genes related to monogenic diabetes, identifying two additional rare variants in HNF1A and GCK associated with fivefold and eightfold increased T2D risk, respectively, the effects of which were modified by the individual's polygenic risk score. For 21% of the variants with conflicting interpretations or uncertain significance in ClinVar, we provided support of being benign based on their lack of association with T2D. Our work provides a framework for using rare variant GWASs to identify large-effect variants and assess variant pathogenicity in monogenic diabetes genes.

    View details for DOI 10.1038/s41588-024-01947-9

    View details for PubMedID 39379762

  • HumanIslets.com: Improving accessibility, integration, and usability of human research islet data. Cell metabolism Ewald, J. D., Lu, Y., Ellis, C. E., Worton, J., Kolic, J., Sasaki, S., Zhang, D., Dos Santos, T., Spigelman, A. F., Bautista, A., Dai, X., Lyon, J. G., Smith, N. P., Wong, J. M., Rajesh, V., Sun, H., Sharp, S. A., Rogalski, J. C., Moravcova, R., Cen, H. H., Manning Fox, J. E., HumanIslets.com Consortium,,, Atlas, E., Bruin, J. E., Mulvihill, E. E., Verchere, C. B., Foster, L. J., Gloyn, A. L., Johnson, J. D., Pepper, A. R., Lynn, F. C., Xia, J., MacDonald, P. E. 2024

    Abstract

    HumanIslets.com supports diabetes research by offering easy access to islet phenotyping data, analysis tools, and data download. It includes molecular omics, islet and cellular function assays, tissue processing metadata, and phenotypes from 547 donors. As it expands, the resource aims to improve human islet data quality, usability, and accessibility.

    View details for DOI 10.1016/j.cmet.2024.09.001

    View details for PubMedID 39357523

  • Diabetes mellitus-Progress and opportunities in the evolving epidemic. Cell Abel, E. D., Gloyn, A. L., Evans-Molina, C., Joseph, J. J., Misra, S., Pajvani, U. B., Simcox, J., Susztak, K., Drucker, D. J. 2024; 187 (15): 3789-3820

    Abstract

    Diabetes, a complex multisystem metabolic disorder characterized by hyperglycemia, leads to complications that reduce quality of life and increase mortality. Diabetes pathophysiology includes dysfunction of beta cells, adipose tissue, skeletal muscle, and liver. Type 1 diabetes (T1D) results from immune-mediated beta cell destruction. The more prevalent type 2 diabetes (T2D) is a heterogeneous disorder characterized by varying degrees of beta cell dysfunction in concert with insulin resistance. The strong association between obesity and T2D involves pathways regulated by the central nervous system governing food intake and energy expenditure, integrating inputs from peripheral organs and the environment. The risk of developing diabetes or its complications represents interactions between genetic susceptibility and environmental factors, including the availability of nutritious food and other social determinants of health. This perspective reviews recent advances in understanding the pathophysiology and treatment of diabetes and its complications, which could alter the course of this prevalent disorder.

    View details for DOI 10.1016/j.cell.2024.06.029

    View details for PubMedID 39059357

  • A global initiative to deliver precision health in diabetes. Nature medicine Cefalu, W. T., Franks, P. W., Rosenblum, N. D., Zaghloul, N. A., Florez, J. C., Giorgino, F., Ji, L., Ma, R. C., Mathieu, C., Misra, S., Ramirez, A. H., Roden, M., Scherer, P. E., Sheu, W. H., Stehouwer, C. D., Woo, M., Pragnell, M., Anand, S. S., Carnethon, M., Chambers, J. C., Dennis, J. M., Gloyn, A. L., Herder, C., Holt, R. I., Manuel, D. G., Redondo, M. J., Tandon, N., Tsang, J. S., Udler, M. S., Rich, S. S. 2024

    View details for DOI 10.1038/s41591-024-03032-4

    View details for PubMedID 38992126

    View details for PubMedCentralID 9522691

  • Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease. Cell metabolism Kolic, J., Sun, W. G., Cen, H. H., Ewald, J. D., Rogalski, J. C., Sasaki, S., Sun, H., Rajesh, V., Xia, Y. H., Moravcova, R., Skovsø, S., Spigelman, A. F., Manning Fox, J. E., Lyon, J., Beet, L., Xia, J., Lynn, F. C., Gloyn, A. L., Foster, L. J., MacDonald, P. E., Johnson, J. D. 2024; 36 (7): 1619-1633.e5

    Abstract

    Population-level variation and mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized. We defined prototypical insulin secretion responses to three macronutrients in islets from 140 cadaveric donors, including those with type 2 diabetes. The majority of donors' islets exhibited the highest insulin response to glucose, moderate response to amino acid, and minimal response to fatty acid. However, 9% of donors' islets had amino acid responses, and 8% had fatty acid responses that were larger than their glucose-stimulated insulin responses. We leveraged this heterogeneity and used multi-omics to identify molecular correlates of nutrient responsiveness, as well as proteins and mRNAs altered in type 2 diabetes. We also examined nutrient-stimulated insulin release from stem cell-derived islets and observed responsiveness to fat but not carbohydrate or protein-potentially a hallmark of immaturity. Understanding the diversity of insulin responses to carbohydrate, protein, and fat lays the groundwork for personalized nutrition.

    View details for DOI 10.1016/j.cmet.2024.06.001

    View details for PubMedID 38959864

Mission Statement

Our mission is to improve understanding of pancreatic islet cell dysfunction in type 2 diabetes using human genetics as a tool to uncover causal disease mechanisms and shed light on potential targets for therapeutic development.

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