Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

John R. B. Perry; Benjamin F. Voight; Loic Yengo; Najaf Amin; Josee Dupuis; Martha Ganser; Harald Grallert; Pau Navarro; Man Li; Lu Qi; Valgerdur Steinthorsdottir; Robert A. Scott; Peter Almgren; Dan E. Arking; Yurii Aulchenko; Beverley Balkau; Rafn Benediktsson; Richard N. Bergman; Eric Boerwinkle; Lori Bonnycastle; Noel P. Burtt; Harry Campbell; Guillaume Charpentier; Francis S. Collins; Christian Gieger; Todd Green; Samy Hadjadj; Andrew T. Hattersley; Christian Herder; Albert Hofman; Andrew D. Johnson; Anna Kottgen; Peter Kraft; Yann Labrune; Claudia Langenberg; Alisa K. Manning; Karen L. Mohlke; Andrew P. Morris; Ben Oostra; James Pankow; Ann-Kristin Petersen; Peter P. Pramstaller; Inga Prokopenko; Wolfgang Rathmann; William Rayner; Michael Roden; Igor Rudan; Denis Rybin; Laura J. Scott; Gunnar Sigurdsson; Rob Sladek; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Jaakko Tuomilehto; Andre G. Uitterlinden; Sidonie Vivequin; Michael N. Weedon; Alan F. Wright; Frank B. Hu; Thomas Illig; Linda Kao; James B. Meigs; James F. Wilson; Kari Stefansson; Cornelia van Duijn; David Altschuler; Andrew D. Morris; Michael Boehnke; Mark I. McCarthy; Philippe Froguel; Colin N. A. Palmer; Nicholas J. Wareham; Leif Groop; Timothy M. Frayling; Stephane Cauchi

doi:10.1371/journal.pgen.1002741

Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

John R. B. Perry, Benjamin F. Voight, Loic Yengo, Najaf Amin, Josee Dupuis, Martha Ganser, Harald Grallert, Pau Navarro, Man Li, Lu Qi, Valgerdur Steinthorsdottir, Robert A. Scott, Peter Almgren, Dan E. Arking, Yurii Aulchenko, Beverley Balkau, Rafn Benediktsson, Richard N. Bergman, Eric Boerwinkle, Lori BonnycastleNoel P. Burtt, Harry Campbell, Guillaume Charpentier, Francis S. Collins, Christian Gieger, Todd Green, Samy Hadjadj, Andrew T. Hattersley, Christian Herder, Albert Hofman, Andrew D. Johnson, Anna Kottgen, Peter Kraft, Yann Labrune, Claudia Langenberg, Alisa K. Manning, Karen L. Mohlke, Andrew P. Morris, Ben Oostra, James Pankow, Ann-Kristin Petersen, Peter P. Pramstaller, Inga Prokopenko, Wolfgang Rathmann, William Rayner, Michael Roden, Igor Rudan, Denis Rybin, Laura J. Scott, Gunnar Sigurdsson, Rob Sladek, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jaakko Tuomilehto, Andre G. Uitterlinden, Sidonie Vivequin, Michael N. Weedon, Alan F. Wright, Frank B. Hu, Thomas Illig, Linda Kao, James B. Meigs, James F. Wilson, Kari Stefansson, Cornelia van Duijn, David Altschuler, Andrew D. Morris, Michael Boehnke, Mark I. McCarthy, Philippe Froguel, Colin N. A. Palmer, Nicholas J. Wareham, Leif Groop, Timothy M. Frayling, Stephane Cauchi

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Abstract

Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m(2)) compared to obese cases (BMI >= 30 Kg/m(2)). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m(2)) or 4,123 obese cases (BMI >= 30 kg/m(2)), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4610 29, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A-previously identified in South Asians but not Europeans-was associated with type 2 diabetes in obese cases (P = 1.3 x 10(-8), OR= 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2 x 10(-14). This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2 x 10(-16). This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.

Original language	English
Journal	PLoS Genetics
Volume	8
Issue number	5
DOIs	https://doi.org/10.1371/journal.pgen.1002741
Publication status	Published - 2012

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Endocrinology and Diabetes

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10.1371/journal.pgen.1002741

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Perry, J. R. B., Voight, B. F., Yengo, L., Amin, N., Dupuis, J., Ganser, M., Grallert, H., Navarro, P., Li, M., Qi, L., Steinthorsdottir, V., Scott, R. A., Almgren, P., Arking, D. E., Aulchenko, Y., Balkau, B., Benediktsson, R., Bergman, R. N., Boerwinkle, E., ... Cauchi, S. (2012). Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases. PLoS Genetics, 8(5). https://doi.org/10.1371/journal.pgen.1002741

@article{065336c14e0b47629502a33a047533a0,

title = "Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases",

abstract = "Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m(2)) compared to obese cases (BMI >= 30 Kg/m(2)). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m(2)) or 4,123 obese cases (BMI >= 30 kg/m(2)), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4610 29, OR = 1.13 [95\% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95\% CI 1.00-1.06]). A variant in HMG20A-previously identified in South Asians but not Europeans-was associated with type 2 diabetes in obese cases (P = 1.3 x 10(-8), OR= 1.11 [95\% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95\% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95\% CI 1.10-1.17], P = 3.2 x 10(-14). This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95\% CI 1.05-1.08], P = 2.2 x 10(-16). This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.",

author = "Perry, \{John R. B.\} and Voight, \{Benjamin F.\} and Loic Yengo and Najaf Amin and Josee Dupuis and Martha Ganser and Harald Grallert and Pau Navarro and Man Li and Lu Qi and Valgerdur Steinthorsdottir and Scott, \{Robert A.\} and Peter Almgren and Arking, \{Dan E.\} and Yurii Aulchenko and Beverley Balkau and Rafn Benediktsson and Bergman, \{Richard N.\} and Eric Boerwinkle and Lori Bonnycastle and Burtt, \{Noel P.\} and Harry Campbell and Guillaume Charpentier and Collins, \{Francis S.\} and Christian Gieger and Todd Green and Samy Hadjadj and Hattersley, \{Andrew T.\} and Christian Herder and Albert Hofman and Johnson, \{Andrew D.\} and Anna Kottgen and Peter Kraft and Yann Labrune and Claudia Langenberg and Manning, \{Alisa K.\} and Mohlke, \{Karen L.\} and Morris, \{Andrew P.\} and Ben Oostra and James Pankow and Ann-Kristin Petersen and Pramstaller, \{Peter P.\} and Inga Prokopenko and Wolfgang Rathmann and William Rayner and Michael Roden and Igor Rudan and Denis Rybin and Scott, \{Laura J.\} and Gunnar Sigurdsson and Rob Sladek and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Jaakko Tuomilehto and Uitterlinden, \{Andre G.\} and Sidonie Vivequin and Weedon, \{Michael N.\} and Wright, \{Alan F.\} and Hu, \{Frank B.\} and Thomas Illig and Linda Kao and Meigs, \{James B.\} and Wilson, \{James F.\} and Kari Stefansson and \{van Duijn\}, Cornelia and David Altschuler and Morris, \{Andrew D.\} and Michael Boehnke and McCarthy, \{Mark I.\} and Philippe Froguel and Palmer, \{Colin N. A.\} and Wareham, \{Nicholas J.\} and Leif Groop and Frayling, \{Timothy M.\} and Stephane Cauchi",

year = "2012",

doi = "10.1371/journal.pgen.1002741",

language = "English",

volume = "8",

journal = "PLoS Genetics",

issn = "1553-7404",

publisher = "Public Library of Science (PLoS)",

number = "5",

}

Perry, JRB, Voight, BF, Yengo, L, Amin, N, Dupuis, J, Ganser, M, Grallert, H, Navarro, P, Li, M, Qi, L, Steinthorsdottir, V, Scott, RA, Almgren, P, Arking, DE, Aulchenko, Y, Balkau, B, Benediktsson, R, Bergman, RN, Boerwinkle, E, Bonnycastle, L, Burtt, NP, Campbell, H, Charpentier, G, Collins, FS, Gieger, C, Green, T, Hadjadj, S, Hattersley, AT, Herder, C, Hofman, A, Johnson, AD, Kottgen, A, Kraft, P, Labrune, Y, Langenberg, C, Manning, AK, Mohlke, KL, Morris, AP, Oostra, B, Pankow, J, Petersen, A-K, Pramstaller, PP, Prokopenko, I, Rathmann, W, Rayner, W, Roden, M, Rudan, I, Rybin, D, Scott, LJ, Sigurdsson, G, Sladek, R, Thorleifsson, G, Thorsteinsdottir, U, Tuomilehto, J, Uitterlinden, AG, Vivequin, S, Weedon, MN, Wright, AF, Hu, FB, Illig, T, Kao, L, Meigs, JB, Wilson, JF, Stefansson, K, van Duijn, C, Altschuler, D, Morris, AD, Boehnke, M, McCarthy, MI, Froguel, P, Palmer, CNA, Wareham, NJ, Groop, L, Frayling, TM & Cauchi, S 2012, 'Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases', PLoS Genetics, vol. 8, no. 5. https://doi.org/10.1371/journal.pgen.1002741

TY - JOUR

T1 - Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

AU - Perry, John R. B.

AU - Voight, Benjamin F.

AU - Yengo, Loic

AU - Amin, Najaf

AU - Dupuis, Josee

AU - Ganser, Martha

AU - Grallert, Harald

AU - Navarro, Pau

AU - Li, Man

AU - Qi, Lu

AU - Steinthorsdottir, Valgerdur

AU - Scott, Robert A.

AU - Almgren, Peter

AU - Arking, Dan E.

AU - Aulchenko, Yurii

AU - Balkau, Beverley

AU - Benediktsson, Rafn

AU - Bergman, Richard N.

AU - Boerwinkle, Eric

AU - Bonnycastle, Lori

AU - Burtt, Noel P.

AU - Campbell, Harry

AU - Charpentier, Guillaume

AU - Collins, Francis S.

AU - Gieger, Christian

AU - Green, Todd

AU - Hadjadj, Samy

AU - Hattersley, Andrew T.

AU - Herder, Christian

AU - Hofman, Albert

AU - Johnson, Andrew D.

AU - Kottgen, Anna

AU - Kraft, Peter

AU - Labrune, Yann

AU - Langenberg, Claudia

AU - Manning, Alisa K.

AU - Mohlke, Karen L.

AU - Morris, Andrew P.

AU - Oostra, Ben

AU - Pankow, James

AU - Petersen, Ann-Kristin

AU - Pramstaller, Peter P.

AU - Prokopenko, Inga

AU - Rathmann, Wolfgang

AU - Rayner, William

AU - Roden, Michael

AU - Rudan, Igor

AU - Rybin, Denis

AU - Scott, Laura J.

AU - Sigurdsson, Gunnar

AU - Sladek, Rob

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Tuomilehto, Jaakko

AU - Uitterlinden, Andre G.

AU - Vivequin, Sidonie

AU - Weedon, Michael N.

AU - Wright, Alan F.

AU - Hu, Frank B.

AU - Illig, Thomas

AU - Kao, Linda

AU - Meigs, James B.

AU - Wilson, James F.

AU - Stefansson, Kari

AU - van Duijn, Cornelia

AU - Altschuler, David

AU - Morris, Andrew D.

AU - Boehnke, Michael

AU - McCarthy, Mark I.

AU - Froguel, Philippe

AU - Palmer, Colin N. A.

AU - Wareham, Nicholas J.

AU - Groop, Leif

AU - Frayling, Timothy M.

AU - Cauchi, Stephane

PY - 2012

Y1 - 2012

N2 - Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m(2)) compared to obese cases (BMI >= 30 Kg/m(2)). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m(2)) or 4,123 obese cases (BMI >= 30 kg/m(2)), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4610 29, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A-previously identified in South Asians but not Europeans-was associated with type 2 diabetes in obese cases (P = 1.3 x 10(-8), OR= 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2 x 10(-14). This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2 x 10(-16). This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.

AB - Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m(2)) compared to obese cases (BMI >= 30 Kg/m(2)). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m(2)) or 4,123 obese cases (BMI >= 30 kg/m(2)), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4610 29, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A-previously identified in South Asians but not Europeans-was associated with type 2 diabetes in obese cases (P = 1.3 x 10(-8), OR= 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2 x 10(-14). This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2 x 10(-16). This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.

UR - https://www.scopus.com/pages/publications/84863670156

U2 - 10.1371/journal.pgen.1002741

DO - 10.1371/journal.pgen.1002741

M3 - Article

C2 - 22693455

SN - 1553-7404

VL - 8

JO - PLoS Genetics

JF - PLoS Genetics

IS - 5

ER -

Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

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