Skip to main content Accessibility help

Noncoding Variations in the Gene Encoding Ceramide Synthase 6 are Associated with Type 2 Diabetes in a Large Indigenous Australian Pedigree

  • David A. Good (a1), David L. Duffy (a2), Manuela Good (a1), Cheng Xia Guo (a1), Frances Busfield (a1), Anthony Shaw (a1) and Joanne T. E. Shaw (a1) (a2)...


Type 2 diabetes (T2D) is a chronic disease that disproportionately affects Indigenous Australians. We have previously reported the localization of a novel T2D locus by linkage analysis to chromosome 2q24 in a large admixed Indigenous Australian pedigree (Busfield et al. (2002). American Journal of Human Genetics, 70, 349–357). Here we describe fine mapping of this region in this pedigree, with the identification of SNPs showing strong association with T2D: rs3845724 (diabetes p = 7 × 10−4), rs4668106 (diabetes p = 9 × 10−4) and rs529002 (plasma glucose p = 3 × 10−4). These associations were successfully replicated in an independent collection of Indigenous Australian T2D cases and controls. These SNPs all lie within the gene encoding ceramide synthase 6 (CERS6) and thus may regulate ceramide synthesis.


Corresponding author

*Author for correspondence: Joanne T. E. Shaw, Email:


Hide All
Baerenwald, D. A., Bonnefond, A., Bouatia-Naji, N., Flemming, B. P., Umunakwe, O. C., Oeser, J. K., … O’Brien, R. M. (2013). Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels. Diabetologia, 56, 13061316.
Bastian, P. (1979). Coronary heart disease in tribal Aborigines — The West Kimberley survey. Australian and New Zealand Journal of Medicine, 9, 284292.
Bell, G. I., Pilkis, S. J., Weber, I. T., & Polonsky, K. S. (1996). Glucokinase mutations, insulin secretion, and diabetes mellitus. Annual Review of Physiology, 58, 171186.
Bouatia-Naji, N., Rocheleau, G., Van Lommel, L., Lemaire, K., Schuit, F., Cavalcanti-Proenca, C., … Froguel, P. (2008). A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels. Science, 320, 10851088.
Browning, B. L., Zhou, Y., & Browning, S. R. (2018). A one-penny imputed genome from next generation reference panels. American Journal of Human Genetics, 103, 338348.
Busfield, F., Duffy, D. L., Kesting, J. B., Walker, S. M., Lovelock, P. K., Good, D., … Shaw, J. T. E. (2002). A genome-wide search for type diabetes susceptibility in Indigenous Australians: Linkage to a novel region on human chromosome 2q. American Journal of Human Genetics, 70, 349357.
Chen, H., Wang, C., Conomos, M. P., Stilp, A. M., Li, Z., Sofer, T., … Lin, X. (2016). Control for population structure and relatedness for binary traits in genetic association studies using logistic mixed models. American Journal of Human Genetics, 98, 653666.
Conomos, M. P., Gogarten, S. M., Brown, L., Chen, H., Rice, K., Sofer, T., … Yu, C. (2019). GENESIS: GENetic EStimation and Inference in Structured samples (GENESIS): Statistical methods for analyzing genetic data from samples with population structure and/or relatedness . R package version 2.12.4. Retrieved from
DeFronzo, R. A. (1988). Lilly Lecture 1987. The triumvirate: Beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes, 37, 667687.
Duffy, D. L. (1997). Sib-pair: A program for non-parametric linkage/association analysis. American Journal of Human Genetics, 61, 197.
Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, A. U., Barroso, I. (2010). New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature Genetics, 42(2), 105116.
Fumagalli, M., Moltke, I., Garup, N., Racimo, F., Bjerregaard, P., Jorgensen, M. E., … Neilsen, R. (2015). Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science, 349, 13431347.
Galadari, S., Rahman, A., Pallichankandy, S., Galadari, A., & Thayyullathil, F. (2013). Role of ceramide in diabetes mellitus: Evidence and mechanisms. Lipids in Health and Disease, 12, 98.
Garup, N., Moltke, I., Andersen, M. K., Dalby, M., Vitting-Seerup, K., Kern, T., … Hansen, T. (2018). Loss-of-function variants in ADCY3 increases risk of obesity and type 2 diabetes. Nature Genetics, 50, 172174.
Gault, A., O’Dea, K., Rowley, K. G., McLeay, T., & Traianedes, K. (1996). Abnormal glucose tolerance and other coronary heart disease risk factors in an isolated Aboriginal community in central Australia. Diabetes Care, 19, 12691273.
GTEx Consortium. (2013). The Genotype-Tissue Expression (GTEx) project. Nature Genetics, 45, 580585.
Guest, C. S., O’Dea, K, Hopper, J. L., & Larkins, R. G. (1993). Hyperinsulinaemia and obesity in Aborigines of south-eastern Australia, with comparisons from rural and urban Europid populations. Diabetes Research and Clinical Practice, 20, 155164.
Hayman, N. (1997). Cardiovascular disease amongst Indigenous Australians. Aboriginal and Islander Health Worker Journal, 21, 1517.
Holmes, R. S., Barron, K. A., & Krupenko, N. I. (2018). Ceramide synthase 6: Comparative analysis, phylogeny and evolution. Biomolecules, 8, 111.
Horikawa, Y., Iwasaki, N., Hara, M., Furuta, H., Hinokio, Y., Cockburn, B. N., … Bell, G. I. (1997). Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nature Genetics, 17, 384385.
International HapMap Consortium (IHMC). (2005). A haplotype map of the human genome. Nature, 437, 12991320.
Konstantynowicz-Nowicka, K., Harasim, E., Baranowski, M., & Chabowski, A. (2015). New evidence for role of ceramide in the development of hepatic insulin resistance. PLoS One, 10, e0116858.
Lange, K., Papp, J. C., Sinsheimer, J. S., Sripracha, R., Zhou, H., & Sobel, E. M. (2013). Mendel: The Swiss army knife of genetic analysis programs. Bioinformatics, 29, 15681570.
Maassen, J. A., & Kadowaki, T. (1996). Maternally inherited diabetes and deafness: A new diabetes subtype. Diabetologia, 39, 375382.
Mahajan, A., Taliun, D., Thurner, M., Robertson, N. R., Torres, J. M., Rayner, N. W., … McCarthy, M. I. (2018). Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nature Genetics, 50, 15051513.
Malecki, M. T., Jhala, U. S., Antonellis, A., Fields, L., Doria, A., Orban, T., … Krolewski, A. S. (1999). Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nature Genetics, 23, 323328.
Manning, A. K., Hivert, M. F., Scott, R. A., Grimsby, J. L., Bouatia-Naji, N., Chen, H., … Langenberg, C. (2012). A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nature Genetics, 44, 659669.
Miguel-Escalada, I., Bonàs-Guarch, S., Cebola, I., Ponsa-Cobas, J., Mendieta-Esteban, J., Rolando, D. M. Y., … Ferrer, J. (2018). Human pancreatic islet 3D chromatin architecture provides insights into the genetics of type 2 diabetes. bioRxiv 400291.
Miller, S. A., Dykes, D. D., & Polesky, H. F. (1988). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Research, 16, 1215.
Minster, R. L., Hawley, N. L., Su, C. T., Sun, G., Kershaw, E. E., Cheng, H., … McGarvey, S. T. (2016). A thrifty variant in CREBRF strongly influences body mass index in Samoans. Nature Genetics, 48, 10491054.
Moltke, I., Grarup, N., Jorgensen, M. E., Bjerregaard, P., Treebak, J. T., Fumagalli, M., … Hansen, T. (2014). A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature, 512, 190193.
Moskvina, V., & Schmidt, K. M. (2008). On multiple-testing correction in genome-wide association studies. Genetic Epidemiology, 32, 567573.
Mularoni, L., Ramos, M., & Pasquali, L. (2017). The pancreatic islet regulome browser. Frontiers in Genetics, 8, 13.
National Center for Biotechnology Information (NCBI). (2019). Phenotype-genotype integrator. Retrieved from
O’Dea, K. (1991). Westernisation, insulin resistance and diabetes in Australian Aborigines. Medical Journal of Australia, 155, 258264.
O’Dea, K. (1992). Diabetes in Australian Aborigines: Impact of the western diet and life style. Journal of Internal Medicine, 232, 103117.
O’Dea, K., Lion, R. J., Lee, A., Traianedes, K., Hopper, J. L., & Rae, C. (1990). Diabetes, hyperinsulinemia, and hyperlipidemia in small Aboriginal community in northern Australia. Diabetes Care, 13, 830835.
O’Dea, K., Patel, M., Kubisch, D., Hopper, J., & Traianedes, K. (1993). Obesity, diabetes, and hyperlipidemia in a central Australian Aboriginal community with a long history of acculturation. Diabetes Care, 16, 10041010.
Raftery, A., Hoeting, J., Volinsky, P., Painter, I., & Yeung, K. Y. (2006). BMA: Bayesian model averaging R package version 3.03. Retrieved from,
R Core Team. (2019). R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. Retrieved from
Steiner, D. F., Tager, H. S., Nanjo, K., Chan, S. J., & Rubenstein, A. H. (1995). Familial syndromes of hyperproinsulinaemia and hyperinsulinaemia with mild diabetes. In Scriver, C. R., Beaudet, A. L., Sly, W. S., & Valle, D. (Eds.), The metabolic and molecular bases of inherited disease (pp. 897904). New York, NY: McGraw-Hill.
Stoffers, D. A., Zinkin, N. T., Stanojevic, V., Clarke, W. L., & Habener, J. F. (1997). Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nature Genetics, 15, 106110.
Suzuki, K., Akiyama, M., Ishigaki, K., Kanai, M., Hosoe, J., Shojima, N., … Kadowaki, T. (2019). Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population. Nature Genetics, 51, 379386.
Taylor, S. I. (1995). Diabetes mellitus. In Scriver, C. R., Beaudet, A. L., Sly, W. S., & Valle, D. (Eds.), The metabolic and molecular bases of inherited disease (pp. 843896). New York, NY: McGraw-Hill.
Williams, D. R., Moffitt, P. S., Fisher, J. S., & Bashir, H. V. (1987). Diabetes and glucose tolerance in New South Wales coastal Aborigines: possible effects of non-Aboriginal genetic admixture. Diabetologia, 30, 7277.
Yamagata, K., Furuta, H., Oda, N., Kaisaki, P. J., Menzel, S., Cox, N. J., … Bell, G. I. (1996). Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature, 384, 458460.
Yamagata, K., Oda, N., Kaisaki, P. J., Menzel, S., Furuta, H., Vaxillaire, M., … Bell, G. I. (1996). Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature, 384, 455458.
Zimmet, P., & Welborn, T. (2001). The final report of the Australian Diabetes and Obesity Study (AusDiab).. Canberra, Australia: Commonwealth Department of Health and Aged Care.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed