Publications

Professor of Pediatrics (Endocrinology) and, by courtesy, of Genetics

Publications

  • Monogenic diabetes: a gateway to precision medicine in diabetes. The Journal of clinical investigation Zhang, H., Colclough, K., Gloyn, A. L., Pollin, T. I. 2021; 131 (3)

    Abstract

    Monogenic diabetes refers to diabetes mellitus (DM) caused by a mutation in a single gene and accounts for approximately 1%-5% of diabetes. Correct diagnosis is clinically critical for certain types of monogenic diabetes, since the appropriate treatment is determined by the etiology of the disease (e.g., oral sulfonylurea treatment of HNF1A/HNF4A-diabetes vs. insulin injections in type 1 diabetes). However, achieving a correct diagnosis requires genetic testing, and the overlapping of the clinical features of monogenic diabetes with those of type 1 and type 2 diabetes has frequently led to misdiagnosis. Improvements in sequencing technology are increasing opportunities to diagnose monogenic diabetes, but challenges remain. In this Review, we describe the types of monogenic diabetes, including common and uncommon types of maturity-onset diabetes of the young, multiple causes of neonatal DM, and syndromic diabetes such as Wolfram syndrome and lipodystrophy. We also review methods of prioritizing patients undergoing genetic testing, and highlight existing challenges facing sequence data interpretation that can be addressed by forming collaborations of expertise and by pooling cases.

    View details for DOI 10.1172/JCI142244

    View details for PubMedID 33529164

  • A Multi-omic Integrative Scheme Characterizes Tissues of Action at Loci Associated with Type 2 Diabetes. American journal of human genetics Torres, J. M., Abdalla, M., Payne, A., Fernandez-Tajes, J., Thurner, M., Nylander, V., Gloyn, A. L., Mahajan, A., McCarthy, M. I. 2020

    Abstract

    Resolving the molecular processes that mediate genetic risk remains a challenge because most disease-associated variants are non-coding and functional characterization of these signals requires knowledge of the specific tissues and cell-types in which they operate. To address this challenge, we developed a framework for integrating tissue-specific gene expression and epigenomic maps to obtain "tissue-of-action" (TOA) scores for each association signal by systematically partitioning posterior probabilities from Bayesian fine-mapping. We applied this scheme to credible set variants for 380 association signals from a recent GWAS meta-analysis of type 2 diabetes (T2D) in Europeans. The resulting tissue profiles underscored a predominant role for pancreatic islets and, to a lesser extent, adipose and liver, particularly among signals with greater fine-mapping resolution. We incorporated resulting TOA scores into a rule-based classifier and validated the tissue assignments through comparison with data from cis-eQTL enrichment, functional fine-mapping, RNA co-expression, and patterns of physiological association. In addition to implicating signals with a single TOA, we found evidence for signals with shared effects in multiple tissues as well as distinct tissue profiles between independent signals within heterogeneous loci. Lastly, we demonstrated that TOA scores can be directly coupled with eQTL colocalization to further resolve effector transcripts at T2D signals. This framework guides mechanistic inference by directing functional validation studies to the most relevant tissues and can gain power as fine-mapping resolution and cell-specific annotations become richer. This method is generalizable to all complex traits with relevant annotation data and is made available as an R package.

    View details for DOI 10.1016/j.ajhg.2020.10.009

    View details for PubMedID 33186544

  • Response to Comment on Misra et al. Homozygous Hypomorphic HNF1A Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes. Diabetes Care 2020;43:909-912. Diabetes care Misra, S., Hassanali, N., Bennett, A. J., Juszczak, A., Caswell, R., Colclough, K., Valabhji, J., Ellard, S., Oliver, N. S., Gloyn, A. L. 2020; 43 (10): e155–e156

    View details for DOI 10.2337/dci20-0033

    View details for PubMedID 32958621

  • Identification of type 2 diabetes loci in 433,540 East Asian individuals. Nature Spracklen, C. N., Horikoshi, M., Kim, Y. J., Lin, K., Bragg, F., Moon, S., Suzuki, K., Tam, C. H., Tabara, Y., Kwak, S., Takeuchi, F., Long, J., Lim, V. J., Chai, J., Chen, C., Nakatochi, M., Yao, J., Choi, H. S., Iyengar, A. K., Perrin, H. J., Brotman, S. M., van de Bunt, M., Gloyn, A. L., Below, J. E., Boehnke, M., Bowden, D. W., Chambers, J. C., Mahajan, A., McCarthy, M. I., Ng, M. C., Petty, L. E., Zhang, W., Morris, A. P., Adair, L. S., Akiyama, M., Bian, Z., Chan, J. C., Chang, L., Chee, M., Chen, Y. I., Chen, Y., Chen, Z., Chuang, L., Du, S., Gordon-Larsen, P., Gross, M., Guo, X., Guo, Y., Han, S., Howard, A., Huang, W., Hung, Y., Hwang, M. Y., Hwu, C., Ichihara, S., Isono, M., Jang, H., Jiang, G., Jonas, J. B., Kamatani, Y., Katsuya, T., Kawaguchi, T., Khor, C., Kohara, K., Lee, M., Lee, N. R., Li, L., Liu, J., Luk, A. O., Lv, J., Okada, Y., Pereira, M. A., Sabanayagam, C., Shi, J., Shin, D. M., So, W. Y., Takahashi, A., Tomlinson, B., Tsai, F., van Dam, R. M., Xiang, Y., Yamamoto, K., Yamauchi, T., Yoon, K., Yu, C., Yuan, J., Zhang, L., Zheng, W., Igase, M., Cho, Y. S., Rotter, J. I., Wang, Y., Sheu, W. H., Yokota, M., Wu, J., Cheng, C., Wong, T., Shu, X., Kato, N., Park, K., Tai, E., Matsuda, F., Koh, W., Ma, R. C., Maeda, S., Millwood, I. Y., Lee, J., Kadowaki, T., Walters, R. G., Kim, B., Mohlke, K. L., Sim, X. 2020

    Abstract

    Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.

    View details for DOI 10.1038/s41586-020-2263-3

    View details for PubMedID 32499647

  • Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma. Cell Chung, K. M., Singh, J., Lawres, L., Dorans, K. J., Garcia, C., Burkhardt, D. B., Robbins, R., Bhutkar, A., Cardone, R., Zhao, X., Babic, A., Vayrynen, S. A., Dias Costa, A., Nowak, J. A., Chang, D. T., Dunne, R. F., Hezel, A. F., Koong, A. C., Wilhelm, J. J., Bellin, M. D., Nylander, V., Gloyn, A. L., McCarthy, M. I., Kibbey, R. G., Krishnaswamy, S., Wolpin, B. M., Jacks, T., Fuchs, C. S., Muzumdar, M. D. 2020

    Abstract

    Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.

    View details for DOI 10.1016/j.cell.2020.03.062

    View details for PubMedID 32304665

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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