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, Loïc Yengo, Najaf Amin, Josée Dupuis, Martha Ganser, Harald Grallert, Pau Navarro, Man Li, Lu Qi, Valgerdur Steinthorsdottir, Robert A. Scott, Peter Almgren, Dan Arking, Yurii Aulchenko, Beverley Balkau, Rafn Benediktsson, Richard N. Bergman, Eric Boerwinkle, Lori BonnycastleNoël 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, Stéphane Cauchi

Research output: Contribution to journalArticle

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 (BMI2) compared to obese cases (BMI≥30 Kg/m2). 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 (BMI2) or 4,123 obese cases (BMI≥30 kg/m2), 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 = 8.4×10-9, 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 = 1.3×10-8, 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 = 3.2×10-14. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2×10-16. 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 languageEnglish (US)
Article numbere1002741
JournalPLoS Genetics
Volume8
Issue number5
DOIs
StatePublished - May 2012

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diabetes
noninsulin-dependent diabetes mellitus
Type 2 Diabetes Mellitus
Genetic Predisposition to Disease
loci
obesity
risk factor
odds ratio
body mass
Single Nucleotide Polymorphism
body mass index
allele
Body Mass Index
stratification
risk factors
genome
Obesity
Alleles
Odds Ratio
Genome

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

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Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases. / Perry, John R B; Voight, Benjamin F.; Yengo, Loïc; Amin, Najaf; Dupuis, Josée; Ganser, Martha; Grallert, Harald; Navarro, Pau; Li, Man; Qi, Lu; Steinthorsdottir, Valgerdur; Scott, Robert A.; Almgren, Peter; Arking, Dan; Aulchenko, Yurii; Balkau, Beverley; Benediktsson, Rafn; Bergman, Richard N.; Boerwinkle, Eric; Bonnycastle, Lori; Burtt, Noël P.; Campbell, Harry; Charpentier, Guillaume; Collins, Francis S.; Gieger, Christian; Green, Todd; Hadjadj, Samy; Hattersley, Andrew T.; Herder, Christian; Hofman, Albert; Johnson, Andrew D.; Kottgen, Anna; Kraft, Peter; Labrune, Yann; Langenberg, Claudia; Manning, Alisa K.; Mohlke, Karen L.; Morris, Andrew P.; Oostra, Ben; Pankow, James; Petersen, Ann Kristin; Pramstaller, Peter P.; Prokopenko, Inga; Rathmann, Wolfgang; Rayner, William; Roden, Michael; Rudan, Igor; Rybin, Denis; Scott, Laura J.; Sigurdsson, Gunnar; Sladek, Rob; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tuomilehto, Jaakko; Uitterlinden, Andre G.; Vivequin, Sidonie; Weedon, Michael N.; Wright, Alan F.; Hu, Frank B.; Illig, Thomas; Kao, Linda; Meigs, James B.; Wilson, James F.; Stefansson, Kari; van Duijn, Cornelia; Altschuler, David; Morris, Andrew D.; Boehnke, Michael; McCarthy, Mark I.; Froguel, Philippe; Palmer, Colin N A; Wareham, Nicholas J.; Groop, Leif; Frayling, Timothy M.; Cauchi, Stéphane.

In: PLoS Genetics, Vol. 8, No. 5, e1002741, 05.2012.

Research output: Contribution to journalArticle

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, D, 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, AK, 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, e1002741. https://doi.org/10.1371/journal.pgen.1002741
Perry, John R B ; Voight, Benjamin F. ; Yengo, Loïc ; Amin, Najaf ; Dupuis, Josée ; Ganser, Martha ; Grallert, Harald ; Navarro, Pau ; Li, Man ; Qi, Lu ; Steinthorsdottir, Valgerdur ; Scott, Robert A. ; Almgren, Peter ; Arking, Dan ; Aulchenko, Yurii ; Balkau, Beverley ; Benediktsson, Rafn ; Bergman, Richard N. ; Boerwinkle, Eric ; Bonnycastle, Lori ; Burtt, Noël P. ; Campbell, Harry ; Charpentier, Guillaume ; Collins, Francis S. ; Gieger, Christian ; Green, Todd ; Hadjadj, Samy ; Hattersley, Andrew T. ; Herder, Christian ; Hofman, Albert ; Johnson, Andrew D. ; Kottgen, Anna ; Kraft, Peter ; Labrune, Yann ; Langenberg, Claudia ; Manning, Alisa K. ; Mohlke, Karen L. ; Morris, Andrew P. ; Oostra, Ben ; Pankow, James ; Petersen, Ann Kristin ; Pramstaller, Peter P. ; Prokopenko, Inga ; Rathmann, Wolfgang ; Rayner, William ; Roden, Michael ; Rudan, Igor ; Rybin, Denis ; Scott, Laura J. ; Sigurdsson, Gunnar ; Sladek, Rob ; Thorleifsson, Gudmar ; Thorsteinsdottir, Unnur ; Tuomilehto, Jaakko ; Uitterlinden, Andre G. ; Vivequin, Sidonie ; Weedon, Michael N. ; Wright, Alan F. ; Hu, Frank B. ; Illig, Thomas ; Kao, Linda ; Meigs, James B. ; Wilson, James F. ; Stefansson, Kari ; van Duijn, Cornelia ; Altschuler, David ; Morris, Andrew D. ; Boehnke, Michael ; McCarthy, Mark I. ; Froguel, Philippe ; Palmer, Colin N A ; Wareham, Nicholas J. ; Groop, Leif ; Frayling, Timothy M. ; Cauchi, Stéphane. / Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases. In: PLoS Genetics. 2012 ; Vol. 8, No. 5.
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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 (BMI2) compared to obese cases (BMI≥30 Kg/m2). 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 (BMI2) or 4,123 obese cases (BMI≥30 kg/m2), 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 = 8.4×10-9, 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 = 1.3×10-8, 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 = 3.2×10-14. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95{\%} CI 1.05-1.08], P = 2.2×10-16. 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.",
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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, Loïc

AU - Amin, Najaf

AU - Dupuis, Josée

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

AU - Aulchenko, Yurii

AU - Balkau, Beverley

AU - Benediktsson, Rafn

AU - Bergman, Richard N.

AU - Boerwinkle, Eric

AU - Bonnycastle, Lori

AU - Burtt, Noël 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, Stéphane

PY - 2012/5

Y1 - 2012/5

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 (BMI2) compared to obese cases (BMI≥30 Kg/m2). 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 (BMI2) or 4,123 obese cases (BMI≥30 kg/m2), 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 = 8.4×10-9, 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 = 1.3×10-8, 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 = 3.2×10-14. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2×10-16. 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 (BMI2) compared to obese cases (BMI≥30 Kg/m2). 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 (BMI2) or 4,123 obese cases (BMI≥30 kg/m2), 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 = 8.4×10-9, 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 = 1.3×10-8, 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 = 3.2×10-14. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2×10-16. 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.

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