Letter | Published:

Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico

Nature volume 506, pages 97101 (06 February 2014) | Download Citation

Abstract

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others1, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings2,3,4, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10−13; odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10−4; OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at 50% frequency in Native American samples and 10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.

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Data deposits

Genotype data have been deposited in dbGaP under accession number phs000683.v1.p1. Microarray data used in the ‘55k screen’ is publicly available through the NCBI Gene Expression Omnibus and the Cancer Cell Line Encyclopedia. A list of sample identities and accession numbers are available in the Supplementary Information.

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Acknowledgements

We thank M. Daly, V. Mootha, E. Lander and K. Estrada for comments on the manuscript, B. Voight, A. Segre, J. Pickrell and the Scientific Advisory Board of the SIGMA Project (especially C. Bustamante) for useful discussions, and A. Subramanian and V. Rusu for assistance with expression analyses. This work was conducted as part of the Slim Initiative for Genomic Medicine, a joint US–Mexico project funded by the Carlos Slim Health Institute. The UNAM/INCMNSZ Diabetes Study was supported by Consejo Nacional de Ciencia y Tecnología grants 138826, 128877, CONACyT- SALUD 2009-01-115250, and a grant from Dirección General de Asuntos del Personal Académico, UNAM, IT 214711. The Diabetes in Mexico Study was supported by Consejo Nacional de Ciencia y Tecnología grant 86867 and by Instituto Carlos Slim de la Salud, A.C. The Mexico City Diabetes Study was supported by National Institutes of Health (NIH) grant R01HL24799 and by the Consejo Nacional de Ciencia y Tenologia grants 2092, M9303, F677-M9407, 251M and 2005-C01-14502, SALUD 2010-2-151165. The Multiethnic Cohort was supported by NIH grants CA164973, CA054281 and CA063464. The Singapore Chinese Health Study was funded by the National Medical Research Council of Singapore under its individual research grant scheme and by NIH grants R01 CA55069, R35 CA53890, R01 CA80205 and R01 CA144034. The Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) project was supported by NIH grant U01DK085526. The San Antonio Mexican American Family Studies (SAMAFS) were supported by R01 DK042273, R01 DK047482, R01 DK053889, R01 DK057295, P01 HL045522 and a Veterans Administration Epidemiologic grant to R.A.D. A.L.W. was supported by National Institutes of Health Ruth L. Kirschstein National Research Service Award number F32 HG005944.

Author information

Affiliations

  1. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • Amy L. Williams
    • , Suzanne B. R. Jacobs
    • , Claire Churchhouse
    • , Noël P. Burtt
    • , Jose C. Florez
    • , David Altshuler
    • , Stephan Ripke
    • , Alisa K. Manning
    • , Benjamin Neale
    • , David Reich
    • , Nick Patterson
    • , Jacquelyn Murphy
    • , Monkol Lek
    • , Sriram Sankararaman
    • , Daniel G. MacArthur
    • , Jason Flannick
    •  & Pierre Fontanillas
  2. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Amy L. Williams
    • , David Altshuler
    • , David Reich
    •  & Sriram Sankararaman
  3. Universidad Autonoma Metropolitana, Tlalpan 14387, Mexico City, Mexico.

    • Hortensia Moreno-Macías
  4. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Sección XVI, Tlalpan, 14000 Mexico City, Mexico.

    • Alicia Huerta-Chagoya
    • , María José Gómez-Vázquez
    • , Carlos A. Aguilar-Salinas
    • , Teresa Tusié-Luna
    • , María Luisa Ordóñez-Sánchez
    • , Rosario Rodríguez-Guillén
    • , Ivette Cruz-Bautista
    • , Maribel Rodríguez-Torres
    • , Linda Liliana Muñoz-Hernández
    • , Tamara Sáenz
    • , Donají Gómez
    •  & Ulices Alvirde
  5. Instituto de Investigaciones Biomédicas, UNAM. Unidad de Biología Molecular y Medicina Genómica, UNAM/INCMNSZ, Coyoacán, 04510 Mexico City, Mexico.

    • Alicia Huerta-Chagoya
    • , Teresa Tusié-Luna
    •  & Laura Riba
  6. Instituto Nacional de Medicina Genómica, Tlalpan, 14610 Mexico City, Mexico.

    • Carla Márquez-Luna
    • , Humberto García-Ortíz
    • , Lorena Orozco
    • , Juan Carlos Fernández-López
    • , Sandra Romero-Hidalgo
    • , Irma Aguilar-Delfín
    • , Angélica Martínez-Hernández
    • , Federico Centeno-Cruz
    • , Elvia Mendoza-Caamal
    • , Emilio Córdova
    •  & Xavier Soberón
  7. Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León 66451, México.

    • María José Gómez-Vázquez
  8. Centro de Estudios en Diabetes, Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Publica, 01120 Mexico City, Mexico.

    • Clicerio González-Villalpando
    •  & María Elena González-Villalpando
  9. Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston 02114, Massachusetts, USA.

    • Jose C. Florez
    • , David Altshuler
    •  & Jason Flannick
  10. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Jose C. Florez
    •  & David Altshuler
  11. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.

    • Christopher A. Haiman
    • , Daniel O. Stram
    • , Brian E. Henderson
    •  & Kristine Monroe
  12. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • David Altshuler
  13. Department of Molecular Biology, Harvard Medical School, Boston, Massachusetts 02114, USA.

    • David Altshuler
  14. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

    • David Altshuler
  15. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Stephan Ripke
    • , Benjamin Neale
    • , Monkol Lek
    •  & Daniel G. MacArthur
  16. Unidad de Investigación Médica en Enfermedades Metabólicas, Instituto Mexicano del Seguro Social SXXI, Cuauhtémoc, 06720 Mexico City, Mexico.

    • Cristina Revilla-Monsalve
    •  & Sergio Islas-Andrade
  17. Instituto de Seguridad y Servicios Sociales para los Trabajadores del Estado, Álvaro Obregón, 01030 Mexico City, Mexico.

    • Eunice Rodríguez-Arellano
  18. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.

    • Lynne Wilkens
    • , Laurence N. Kolonel
    •  & Loic Le Marchand
  19. The Genomics Platform, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • Robert C. Onofrio
    • , Wendy M. Brodeur
    • , Diane Gage
    • , Jennifer Franklin
    • , Scott Mahan
    • , Kristin Ardlie
    • , Andrew T. Crenshaw
    • , Wendy Winckler
    • , Timothy Fennell
    • , Yossi Farjoun
    •  & Stacey Gabriel
  20. Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany.

    • Kay Prüfer
    • , Susanna Sawyer
    • , Udo Stenzel
    • , Janet Kelso
    •  & Svante Pääbo
  21. Palaeolithic Department, Institute of Archaeology and Ethnography, Russian Academy of Sciences, Siberian Branch, 630090 Novosibirsk, Russia.

    • Michael V. Shunkov
    •  & Anatoli P. Derevianko
  22. The Metabolite Profiling Platform, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • Shuba Gopal
    • , James A. Grammatikos
    • , Kevin H. Bullock
    • , Amy A. Deik
    • , Amanda L. Souza
    • , Kerry A. Pierce
    •  & Clary B. Clish
  23. Cancer Biology Program, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • Ian C. Smith
  24. University of Minnesota, Minneapolis, Minnesota 55455, USA.

    • Myron D. Gross
    •  & Mark A. Pereira
  25. University of California San Francisco, San Francisco, California 94143, USA.

    • Mark Seielstad
  26. Duke National University of Singapore Graduate Medical School, Singapore 169857, Singapore.

    • Woon-Puay Koh
    •  & E-Shyong Tai
  27. Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore.

    • Woon-Puay Koh
    •  & E-Shyong Tai
  28. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.

    • E-Shyong Tai
  29. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

    • Andrew Morris
  30. Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Tanya M. Teslovich
  31. Department of Medicine, Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

    • Gil Atzmon
  32. Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas 78227, USA.

    • John Blangero
    • , Ravindranath Duggirala
    • , Sobha Puppala
    • , Vidya S. Farook
    •  & Joanne E. Curran
  33. Center for Genomics and Personalized Medicine Research, Center for Diabetes Research, Department of Biochemistry, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.

    • Donald W. Bowden
  34. Department of Epidemiology and Biostatistics, Imperial College London, London SW7 2AZ, UK.

    • John Chambers
  35. Imperial College Healthcare NHS Trust, London W2 1NY, UK.

    • John Chambers
    •  & Jaspal Kooner
  36. Ealing Hospital National Health Service (NHS) Trust, Middlesex UB1 3HW, UK.

    • John Chambers
    •  & Jaspal Kooner
  37. Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do, 200-702 South Korea.

    • Yoon Shin Cho
  38. Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical School, Jerusalem 91120, Israel.

    • Benjamin Glaser
  39. Israel Diabetes Research Group (IDRG), Diabetes Unit, The E. Wolfson Medical Center, Holon 58100, Israel.

    • Benjamin Glaser
  40. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.

    • Craig Hanis
  41. National Heart and Lung Institute (NHLI), Imperial College London, Hammersmith Hospital, London W12 0HS, UK.

    • Jaspal Kooner
  42. Department of Medicine, University of Eastern Finland, Kuopio Campus and Kuopio University Hospital, FI-70211 Kuopio, Finland.

    • Markku Laakso
  43. Center for Genome Science, Korea National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do 363-951, South Korea.

    • Jong-Young Lee
  44. Department of Epidemiology and Public Health, National University of Singapore, Singapore 117597, Singapore.

    • Yik Ying Teo
  45. Centre for Molecular Epidemiology, National University of Singapore, Singapore 117456, Singapore.

    • Yik Ying Teo
  46. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672, Singapore.

    • Yik Ying Teo
  47. Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore 117456, Singapore.

    • Yik Ying Teo
  48. Department of Statistics and Applied Probability, National University of Singapore, Singapore 117546, Singapore.

    • Yik Ying Teo
  49. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.

    • James G. Wilson
  50. Division of Nephrology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.

    • Farook Thameem
    •  & Hanna E. Abboud
  51. Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.

    • Ralph A. DeFronzo
    •  & Christopher P. Jenkinson
  52. Division of Clinical Epidemiology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.

    • Donna M. Lehman
  53. Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • Maria L. Cortes

Consortia

  1. The SIGMA Type 2 Diabetes Consortium

    Writing team

    Analysis team

    Clinical research, study design and metabolic phenotyping: Diabetes in Mexico Study

    Massachusetts General Hospital

    Mexico City Diabetes Study

    Multiethnic Cohort

    UNAM/INCMNSZ Diabetes Study

    Sample quality control and whole-genome genotyping

    Neanderthal analysis team

    Functional analysis and metabolite profiling

    Replication genotyping and analysis: Broad Institute of Harvard and MIT

    Singapore Chinese Health Study

    T2D-GENES Consortium

    Multiethnic Cohort

    Texas Biomedical Research Institute and University of Texas Health Science Center at San Antonio

    Scientific and project management

    Steering committee

Authors

    Contributions

    See the author list for details of author contributions.

    A list of participants and affiliations for the T2D-GENES Consortium and the Broad Genomics Platform is available in the Supplementary Information.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Teresa Tusié-Luna or David Altshuler or David Altshuler or Teresa Tusié-Luna or David Altshuler or David Altshuler or Teresa Tusié-Luna.

    Extended data

    Supplementary information

    PDF files

    1. 1.

      Supplementary Information

      This file contains Supplementary Methods, Supplementary Tables 1-14, Supplementary Notes, list of Subconsortia Authors and additional references.

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    DOI

    https://doi.org/10.1038/nature12828

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