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

A. L. Williams Amy; S. B.R. Jacobs Suzanne; Hortensia Moreno-Macías; Alicia Huerta-Chagoya; Claire Churchhouse; Carla Márquez-Luna; María José Gómez-Vázquez; N. P. Burtt Noël; Carlos A. Aguilar-Salinas; Clicerio González-Villalpando; Jose C. Florez; Lorena Orozco; Teresa Tusié-Luna; David Altshuler; Stephan Ripke; Alisa K. Manning; Humberto García-Ortíz; Benjamin Neale; David Reich; Daniel O. Stram; Juan Carlos Fernández-López; Sandra Romero-Hidalgo; Nick Patterson; Christopher A. Haiman; Irma Aguilar-Delfín; Angélica Martínez-Hernández; Federico Centeno-Cruz; Elvia Mendoza-Caamal; Cristina Revilla-Monsalve; Sergio Islas-Andrade; Emilio Córdova; Eunice Rodríguez-Arellano; Xavier Soberón; J. C. Florez Jose; M. A. González-Villalpando María Elena; Brian E. Henderson; Kristine Monroe; Lynne Wilkens; Laurence N. Kolonel; Loic Le Marchand; Laura Riba; M. A. Ordóñez-Sánchez María Luisa; Rosario Rodríguez-Guillén; Ivette Cruz-Bautista; Maribel Rodríguez-Torres; Linda Liliana Muñoz-Hernández; Tamara Sáenz; Donají Gómez; Ulices Alvirde; Robert C. Onofrio; Wendy M. Brodeur; Diane Gage; Jacquelyn Murphy; Jennifer Franklin; Scott Mahan; Kristin Ardlie; Andrew T. Crenshaw; Wendy Winckler; Kay Prüfer; Michael V. Shunkov; Susanna Sawyer; Udo Stenzel; Janet Kelso; Monkol Lek; Sriram Sankararaman; Daniel G. MacArthur; Anatoli P. Derevianko; Svante Pääbo; Suzanne B.R. Jacobs; Shuba Gopal; James A. Grammatikos; Ian C. Smith; Kevin H. Bullock; Amy A. Deik; Amanda L. Souza; Kerry A. Pierce; Clary B. Clish; Timothy Fennell; Yossi Farjoun; Stacey Gabriel; Myron D. Gross; Mark A. Pereira; Mark Seielstad; Woon Puay Koh; E. Shyong Tai; Jason Flannick; Pierre Fontanillas; Andrew Morris; Tanya M. Teslovich; Gil Atzmon; John Blangero; Donald W. Bowden; John Chambers; Yoon Shin Cho; Ravindranath Duggirala; Benjamin Glaser; Craig Hanis; Jaspal Kooner; Markku Laakso; Jong Young Lee; Yik Ying Teo; James G. Wilson; Sobha Puppala; Vidya S. Farook; Farook Thameem; Hanna E. Abboud; Ralph A. DeFronzo; Christopher P. Jenkinson; Donna M. Lehman; Joanne E. Curran; Maria L. Cortes; C. González-Villalpando Clicerio; L. Orozco Lorena

doi:10.1038/nature12828

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

A. L. Williams Amy, S. B.R. Jacobs Suzanne, Hortensia Moreno-Macías, Alicia Huerta-Chagoya, Claire Churchhouse, Carla Márquez-Luna, María José Gómez-Vázquez, N. P. Burtt Noël, Carlos A. Aguilar-Salinas, Clicerio González-Villalpando, Jose C. Florez, Lorena Orozco, Teresa Tusié-Luna, David Altshuler, Stephan Ripke, Alisa K. Manning, Humberto García-Ortíz, Benjamin Neale, David Reich, Daniel O. StramJuan Carlos Fernández-López, Sandra Romero-Hidalgo, Nick Patterson, Christopher A. Haiman, Irma Aguilar-Delfín, Angélica Martínez-Hernández, Federico Centeno-Cruz, Elvia Mendoza-Caamal, Cristina Revilla-Monsalve, Sergio Islas-Andrade, Emilio Córdova, Eunice Rodríguez-Arellano, Xavier Soberón, J. C. Florez Jose, M. A. González-Villalpando María Elena, Brian E. Henderson, Kristine Monroe, Lynne Wilkens, Laurence N. Kolonel, Loic Le Marchand, Laura Riba, M. A. Ordóñez-Sánchez María Luisa, Rosario Rodríguez-Guillén, Ivette Cruz-Bautista, Maribel Rodríguez-Torres, Linda Liliana Muñoz-Hernández, Tamara Sáenz, Donají Gómez, Ulices Alvirde, Robert C. Onofrio, Wendy M. Brodeur, Diane Gage, Jacquelyn Murphy, Jennifer Franklin, Scott Mahan, Kristin Ardlie, Andrew T. Crenshaw, Wendy Winckler, Kay Prüfer, Michael V. Shunkov, Susanna Sawyer, Udo Stenzel, Janet Kelso, Monkol Lek, Sriram Sankararaman, Daniel G. MacArthur, Anatoli P. Derevianko, Svante Pääbo, Suzanne B.R. Jacobs, Shuba Gopal, James A. Grammatikos, Ian C. Smith, Kevin H. Bullock, Amy A. Deik, Amanda L. Souza, Kerry A. Pierce, Clary B. Clish, Timothy Fennell, Yossi Farjoun, Stacey Gabriel, Myron D. Gross, Mark A. Pereira, Mark Seielstad, Woon Puay Koh, E. Shyong Tai, Jason Flannick, Pierre Fontanillas, Andrew Morris, Tanya M. Teslovich, Gil Atzmon, John Blangero, Donald W. Bowden, John Chambers, Yoon Shin Cho, Ravindranath Duggirala, Benjamin Glaser, Craig Hanis, Jaspal Kooner, Markku Laakso, Jong Young Lee, Yik Ying Teo, James G. Wilson, Sobha Puppala, Vidya S. Farook, Farook Thameem, Hanna E. Abboud, Ralph A. DeFronzo, Christopher P. Jenkinson, Donna M. Lehman, Joanne E. Curran, Maria L. Cortes, C. González-Villalpando Clicerio, L. Orozco Lorena

Research output: Contribution to journal › Article › peer-review

Abstract

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, 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 findings, 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.

Original language	English
Pages (from-to)	97-101
Number of pages	5
Journal	Nature
Volume	506
Issue number	7486
DOIs	https://doi.org/10.1038/nature12828
State	Published - 2014
Externally published	Yes

Bibliographical note

Funding Information:
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 aspartof the SlimInitiativefor GenomicMedicine,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 CarlosSlim de laSalud,A.C. The MexicoCityDiabetes Study was supported byNational 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

Funding Information:
supported by National Institutes of Health Ruth L. Kirschstein National Research Service Award number F32 HG005944.

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Williams Amy, A. L., Jacobs Suzanne, S. B. R., Moreno-Macías, H., Huerta-Chagoya, A., Churchhouse, C., Márquez-Luna, C., Gómez-Vázquez, M. J., Burtt Noël, N. P., Aguilar-Salinas, C. A., González-Villalpando, C., Florez, J. C., Orozco, L., Tusié-Luna, T., Altshuler, D., Ripke, S., Manning, A. K., García-Ortíz, H., Neale, B., Reich, D., ... Orozco Lorena, L. (2014). Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature, 506(7486), 97-101. https://doi.org/10.1038/nature12828

@article{0f166ce3b8ba4cf0b8ab24819a10a295,

title = "Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico",

abstract = "Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, 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 findings, 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.",

author = "{Williams Amy}, {A. L.} and {Jacobs Suzanne}, {S. B.R.} and Hortensia Moreno-Mac{\'i}as and Alicia Huerta-Chagoya and Claire Churchhouse and Carla M{\'a}rquez-Luna and G{\'o}mez-V{\'a}zquez, {Mar{\'i}a Jos{\'e}} and {Burtt No{\"e}l}, {N. P.} and Aguilar-Salinas, {Carlos A.} and Clicerio Gonz{\'a}lez-Villalpando and Florez, {Jose C.} and Lorena Orozco and Teresa Tusi{\'e}-Luna and David Altshuler and Stephan Ripke and Manning, {Alisa K.} and Humberto Garc{\'i}a-Ort{\'i}z and Benjamin Neale and David Reich and Stram, {Daniel O.} and Fern{\'a}ndez-L{\'o}pez, {Juan Carlos} and Sandra Romero-Hidalgo and Nick Patterson and Haiman, {Christopher A.} and Irma Aguilar-Delf{\'i}n and Ang{\'e}lica Mart{\'i}nez-Hern{\'a}ndez and Federico Centeno-Cruz and Elvia Mendoza-Caamal and Cristina Revilla-Monsalve and Sergio Islas-Andrade and Emilio C{\'o}rdova and Eunice Rodr{\'i}guez-Arellano and Xavier Sober{\'o}n and {Florez Jose}, {J. C.} and {Gonz{\'a}lez-Villalpando Mar{\'i}a Elena}, {M. A.} and Henderson, {Brian E.} and Kristine Monroe and Lynne Wilkens and Kolonel, {Laurence N.} and {Le Marchand}, Loic and Laura Riba and {Ord{\'o}{\~n}ez-S{\'a}nchez Mar{\'i}a Luisa}, {M. A.} and Rosario Rodr{\'i}guez-Guill{\'e}n and Ivette Cruz-Bautista and Maribel Rodr{\'i}guez-Torres and Mu{\~n}oz-Hern{\'a}ndez, {Linda Liliana} and Tamara S{\'a}enz and Donaj{\'i} G{\'o}mez and Ulices Alvirde and Onofrio, {Robert C.} and Brodeur, {Wendy M.} and Diane Gage and Jacquelyn Murphy and Jennifer Franklin and Scott Mahan and Kristin Ardlie and Crenshaw, {Andrew T.} and Wendy Winckler and Kay Pr{\"u}fer and Shunkov, {Michael V.} and Susanna Sawyer and Udo Stenzel and Janet Kelso and Monkol Lek and Sriram Sankararaman and MacArthur, {Daniel G.} and Derevianko, {Anatoli P.} and Svante P{\"a}{\"a}bo and Jacobs, {Suzanne B.R.} and Shuba Gopal and Grammatikos, {James A.} and Smith, {Ian C.} and Bullock, {Kevin H.} and Deik, {Amy A.} and Souza, {Amanda L.} and Pierce, {Kerry A.} and Clish, {Clary B.} and Timothy Fennell and Yossi Farjoun and Stacey Gabriel and Gross, {Myron D.} and Pereira, {Mark A.} and Mark Seielstad and Koh, {Woon Puay} and Tai, {E. Shyong} and Jason Flannick and Pierre Fontanillas and Andrew Morris and Teslovich, {Tanya M.} and Gil Atzmon and John Blangero and Bowden, {Donald W.} and John Chambers and Cho, {Yoon Shin} and Ravindranath Duggirala and Benjamin Glaser and Craig Hanis and Jaspal Kooner and Markku Laakso and Lee, {Jong Young} and Teo, {Yik Ying} and Wilson, {James G.} and Sobha Puppala and Farook, {Vidya S.} and Farook Thameem and Abboud, {Hanna E.} and DeFronzo, {Ralph A.} and Jenkinson, {Christopher P.} and Lehman, {Donna M.} and Curran, {Joanne E.} and Cortes, {Maria L.} and {Gonz{\'a}lez-Villalpando Clicerio}, C. and {Orozco Lorena}, L.",

note = "Funding Information: 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 aspartof the SlimInitiativefor GenomicMedicine,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 Tecnolog{\'i}a grants 138826, 128877, CONACyT-SALUD 2009-01-115250, and a grant from Direcci{\'o}n General de Asuntos del Personal Acad{\'e}mico, UNAM, IT 214711. The Diabetes in Mexico Study was supported by Consejo Nacional de Ciencia y Tecnolog{\'i}a grant 86867 and by Instituto CarlosSlim de laSalud,A.C. The MexicoCityDiabetes Study was supported byNational 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 Funding Information: supported by National Institutes of Health Ruth L. Kirschstein National Research Service Award number F32 HG005944.",

year = "2014",

doi = "10.1038/nature12828",

language = "English",

volume = "506",

pages = "97--101",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7486",

}

Williams Amy, AL, Jacobs Suzanne, SBR, Moreno-Macías, H, Huerta-Chagoya, A, Churchhouse, C, Márquez-Luna, C, Gómez-Vázquez, MJ, Burtt Noël, NP, Aguilar-Salinas, CA, González-Villalpando, C, Florez, JC, Orozco, L, Tusié-Luna, T, Altshuler, D, Ripke, S, Manning, AK, García-Ortíz, H, Neale, B, Reich, D, Stram, DO, Fernández-López, JC, Romero-Hidalgo, S, Patterson, N, Haiman, CA, Aguilar-Delfín, I, Martínez-Hernández, A, Centeno-Cruz, F, Mendoza-Caamal, E, Revilla-Monsalve, C, Islas-Andrade, S, Córdova, E, Rodríguez-Arellano, E, Soberón, X, Florez Jose, JC, González-Villalpando María Elena, MA, Henderson, BE, Monroe, K, Wilkens, L, Kolonel, LN, Le Marchand, L, Riba, L, Ordóñez-Sánchez María Luisa, MA, Rodríguez-Guillén, R, Cruz-Bautista, I, Rodríguez-Torres, M, Muñoz-Hernández, LL, Sáenz, T, Gómez, D, Alvirde, U, Onofrio, RC, Brodeur, WM, Gage, D, Murphy, J, Franklin, J, Mahan, S, Ardlie, K, Crenshaw, AT, Winckler, W, Prüfer, K, Shunkov, MV, Sawyer, S, Stenzel, U, Kelso, J, Lek, M, Sankararaman, S, MacArthur, DG, Derevianko, AP, Pääbo, S, Jacobs, SBR, Gopal, S, Grammatikos, JA, Smith, IC, Bullock, KH, Deik, AA, Souza, AL, Pierce, KA, Clish, CB, Fennell, T, Farjoun, Y, Gabriel, S, Gross, MD, Pereira, MA, Seielstad, M, Koh, WP, Tai, ES, Flannick, J, Fontanillas, P, Morris, A, Teslovich, TM, Atzmon, G, Blangero, J, Bowden, DW, Chambers, J, Cho, YS, Duggirala, R, Glaser, B, Hanis, C, Kooner, J, Laakso, M, Lee, JY, Teo, YY, Wilson, JG, Puppala, S, Farook, VS, Thameem, F, Abboud, HE, DeFronzo, RA, Jenkinson, CP, Lehman, DM, Curran, JE, Cortes, ML, González-Villalpando Clicerio, C & Orozco Lorena, L 2014, 'Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico', Nature, vol. 506, no. 7486, pp. 97-101. https://doi.org/10.1038/nature12828

TY - JOUR

T1 - Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico

AU - Williams Amy, A. L.

AU - Jacobs Suzanne, S. B.R.

AU - Moreno-Macías, Hortensia

AU - Huerta-Chagoya, Alicia

AU - Churchhouse, Claire

AU - Márquez-Luna, Carla

AU - Gómez-Vázquez, María José

AU - Burtt Noël, N. P.

AU - Aguilar-Salinas, Carlos A.

AU - González-Villalpando, Clicerio

AU - Florez, Jose C.

AU - Orozco, Lorena

AU - Tusié-Luna, Teresa

AU - Altshuler, David

AU - Ripke, Stephan

AU - Manning, Alisa K.

AU - García-Ortíz, Humberto

AU - Neale, Benjamin

AU - Reich, David

AU - Stram, Daniel O.

AU - Fernández-López, Juan Carlos

AU - Romero-Hidalgo, Sandra

AU - Patterson, Nick

AU - Haiman, Christopher A.

AU - Aguilar-Delfín, Irma

AU - Martínez-Hernández, Angélica

AU - Centeno-Cruz, Federico

AU - Mendoza-Caamal, Elvia

AU - Revilla-Monsalve, Cristina

AU - Islas-Andrade, Sergio

AU - Córdova, Emilio

AU - Rodríguez-Arellano, Eunice

AU - Soberón, Xavier

AU - Florez Jose, J. C.

AU - González-Villalpando María Elena, M. A.

AU - Henderson, Brian E.

AU - Monroe, Kristine

AU - Wilkens, Lynne

AU - Kolonel, Laurence N.

AU - Le Marchand, Loic

AU - Riba, Laura

AU - Ordóñez-Sánchez María Luisa, M. A.

AU - Rodríguez-Guillén, Rosario

AU - Cruz-Bautista, Ivette

AU - Rodríguez-Torres, Maribel

AU - Muñoz-Hernández, Linda Liliana

AU - Sáenz, Tamara

AU - Gómez, Donají

AU - Alvirde, Ulices

AU - Onofrio, Robert C.

AU - Brodeur, Wendy M.

AU - Gage, Diane

AU - Murphy, Jacquelyn

AU - Franklin, Jennifer

AU - Mahan, Scott

AU - Ardlie, Kristin

AU - Crenshaw, Andrew T.

AU - Winckler, Wendy

AU - Prüfer, Kay

AU - Shunkov, Michael V.

AU - Sawyer, Susanna

AU - Stenzel, Udo

AU - Kelso, Janet

AU - Lek, Monkol

AU - Sankararaman, Sriram

AU - MacArthur, Daniel G.

AU - Derevianko, Anatoli P.

AU - Pääbo, Svante

AU - Jacobs, Suzanne B.R.

AU - Gopal, Shuba

AU - Grammatikos, James A.

AU - Smith, Ian C.

AU - Bullock, Kevin H.

AU - Deik, Amy A.

AU - Souza, Amanda L.

AU - Pierce, Kerry A.

AU - Clish, Clary B.

AU - Fennell, Timothy

AU - Farjoun, Yossi

AU - Gabriel, Stacey

AU - Gross, Myron D.

AU - Pereira, Mark A.

AU - Seielstad, Mark

AU - Koh, Woon Puay

AU - Tai, E. Shyong

AU - Flannick, Jason

AU - Fontanillas, Pierre

AU - Morris, Andrew

AU - Teslovich, Tanya M.

AU - Atzmon, Gil

AU - Blangero, John

AU - Bowden, Donald W.

AU - Chambers, John

AU - Cho, Yoon Shin

AU - Duggirala, Ravindranath

AU - Glaser, Benjamin

AU - Hanis, Craig

AU - Kooner, Jaspal

AU - Laakso, Markku

AU - Lee, Jong Young

AU - Teo, Yik Ying

AU - Wilson, James G.

AU - Puppala, Sobha

AU - Farook, Vidya S.

AU - Thameem, Farook

AU - Abboud, Hanna E.

AU - DeFronzo, Ralph A.

AU - Jenkinson, Christopher P.

AU - Lehman, Donna M.

AU - Curran, Joanne E.

AU - Cortes, Maria L.

AU - González-Villalpando Clicerio, C.

AU - Orozco Lorena, L.

N1 - Funding Information: 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 aspartof the SlimInitiativefor GenomicMedicine,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 CarlosSlim de laSalud,A.C. The MexicoCityDiabetes Study was supported byNational 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 Funding Information: supported by National Institutes of Health Ruth L. Kirschstein National Research Service Award number F32 HG005944.

PY - 2014

Y1 - 2014

N2 - Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, 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 findings, 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.

AB - Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, 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 findings, 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.

UR - http://www.scopus.com/inward/record.url?scp=84893716900&partnerID=8YFLogxK

U2 - 10.1038/nature12828

DO - 10.1038/nature12828

M3 - Article

C2 - 24390345

AN - SCOPUS:84893716900

SN - 0028-0836

VL - 506

SP - 97

EP - 101

JO - Nature

JF - Nature

IS - 7486

ER -

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

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