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

JRB Perry; BF Voight; L Yengo; Najaf Amin; J Dupuis; M Ganser; H Grallert; P Navarro; M Li; L Qi; V Steinthorsdottir; RA Scott; P Almgren; DE Arking; Yuriy Aulchenko; B Balkau; R Benediktsson; RN Bergman; E Boerwinkle; L Bonnycastle; NP Burtt; H Campbell; G Charpentier; FS Collins; C Gieger; T Green; S Hadjadj; AT Hattersley; Cindy Herder; Bert Hofman; AD Johnson; A Kottgen; P Kraft; Y Labrune; C Langenberg; AK Manning; KL Mohlke; AP Morris; Ben Oostra; J Pankow; AK Petersen; PP Pramstaller; I Prokopenko; W Rathmann; W Rayner; M Roden; I Rudan; D Rybin; LJ Scott; G Sigurdsson; R Sladek; G Thorleifsson; U Thorsteinsdottir; J Tuomilehto; André Uitterlinden; S Vivequin; MN Weedon; AF Wright; FB Hu; T Illig; L Kao; JB Meigs; JF Wilson; K Stefansson; Cornelia Duijn; D Altschuler; AD Morris; M Boehnke; MI McCarthy; P Froguel; CNA Palmer; NJ Wareham; L Groop; TM Frayling; S 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

JRB Perry, BF Voight, L Yengo, Najaf Amin, J Dupuis, M Ganser, H Grallert, P Navarro, M Li, L Qi, V Steinthorsdottir, RA Scott, P Almgren, DE Arking, Yuriy Aulchenko, B Balkau, R Benediktsson, RN Bergman, E Boerwinkle, L BonnycastleNP Burtt, H Campbell, G Charpentier, FS Collins, C Gieger, T Green, S Hadjadj, AT Hattersley, Cindy Herder, Bert Hofman, AD Johnson, A Kottgen, P Kraft, Y Labrune, C Langenberg, AK Manning, KL Mohlke, AP Morris, Ben Oostra, J Pankow, AK Petersen, PP Pramstaller, I Prokopenko, W Rathmann, W Rayner, M Roden, I Rudan, D Rybin, LJ Scott, G Sigurdsson, R Sladek, G Thorleifsson, U Thorsteinsdottir, J Tuomilehto, André Uitterlinden, S Vivequin, MN Weedon, AF Wright, FB Hu, T Illig, L Kao, JB Meigs, JF Wilson, K Stefansson, Cornelia Duijn, D Altschuler, AD Morris, M Boehnke, MI McCarthy, P Froguel, CNA Palmer, NJ Wareham, L Groop, TM Frayling, S 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	Undefined/Unknown
Journal	PLoS Genetics (print)
Volume	8
Issue number	5
DOIs	https://doi.org/10.1371/journal.pgen.1002741
Publication status	Published - 2012

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Cite this

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., ... 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 (print), 8(5). https://doi.org/10.1371/journal.pgen.1002741

@article{ba2eb7e029d54e249c159d3f2f9c8d2a,

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 = "JRB Perry and BF Voight and L Yengo and Najaf Amin and J Dupuis and M Ganser and H Grallert and P Navarro and M Li and L Qi and V Steinthorsdottir and RA Scott and P Almgren and DE Arking and Yuriy Aulchenko and B Balkau and R Benediktsson and RN Bergman and E Boerwinkle and L Bonnycastle and NP Burtt and H Campbell and G Charpentier and FS Collins and C Gieger and T Green and S Hadjadj and AT Hattersley and Cindy Herder and Bert Hofman and AD Johnson and A Kottgen and P Kraft and Y Labrune and C Langenberg and AK Manning and KL Mohlke and AP Morris and Ben Oostra and J Pankow and AK Petersen and PP Pramstaller and I Prokopenko and W Rathmann and W Rayner and M Roden and I Rudan and D Rybin and LJ Scott and G Sigurdsson and R Sladek and G Thorleifsson and U Thorsteinsdottir and J Tuomilehto and Andr{\'e} Uitterlinden and S Vivequin and MN Weedon and AF Wright and FB Hu and T Illig and L Kao and JB Meigs and JF Wilson and K Stefansson and Cornelia Duijn and D Altschuler and AD Morris and M Boehnke and MI McCarthy and P Froguel and CNA Palmer and NJ Wareham and L Groop and TM Frayling and S Cauchi",

year = "2012",

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

language = "Undefined/Unknown",

volume = "8",

journal = "PLoS Genetics (print)",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "5",

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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, B, 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, A, Vivequin, S, Weedon, MN, Wright, AF, Hu, FB, Illig, T, Kao, L, Meigs, JB, Wilson, JF, Stefansson, K, 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 (print), 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, JRB

AU - Voight, BF

AU - Yengo, L

AU - Amin, Najaf

AU - Dupuis, J

AU - Ganser, M

AU - Grallert, H

AU - Navarro, P

AU - Li, M

AU - Qi, L

AU - Steinthorsdottir, V

AU - Scott, RA

AU - Almgren, P

AU - Arking, DE

AU - Aulchenko, Yuriy

AU - Balkau, B

AU - Benediktsson, R

AU - Bergman, RN

AU - Boerwinkle, E

AU - Bonnycastle, L

AU - Burtt, NP

AU - Campbell, H

AU - Charpentier, G

AU - Collins, FS

AU - Gieger, C

AU - Green, T

AU - Hadjadj, S

AU - Hattersley, AT

AU - Herder, Cindy

AU - Hofman, Bert

AU - Johnson, AD

AU - Kottgen, A

AU - Kraft, P

AU - Labrune, Y

AU - Langenberg, C

AU - Manning, AK

AU - Mohlke, KL

AU - Morris, AP

AU - Oostra, Ben

AU - Pankow, J

AU - Petersen, AK

AU - Pramstaller, PP

AU - Prokopenko, I

AU - Rathmann, W

AU - Rayner, W

AU - Roden, M

AU - Rudan, I

AU - Rybin, D

AU - Scott, LJ

AU - Sigurdsson, G

AU - Sladek, R

AU - Thorleifsson, G

AU - Thorsteinsdottir, U

AU - Tuomilehto, J

AU - Uitterlinden, André

AU - Vivequin, S

AU - Weedon, MN

AU - Wright, AF

AU - Hu, FB

AU - Illig, T

AU - Kao, L

AU - Meigs, JB

AU - Wilson, JF

AU - Stefansson, K

AU - Duijn, Cornelia

AU - Altschuler, D

AU - Morris, AD

AU - Boehnke, M

AU - McCarthy, MI

AU - Froguel, P

AU - Palmer, CNA

AU - Wareham, NJ

AU - Groop, L

AU - Frayling, TM

AU - Cauchi, S

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.

U2 - 10.1371/journal.pgen.1002741

DO - 10.1371/journal.pgen.1002741

M3 - Article

C2 - 22693455

SN - 1553-7390

VL - 8

JO - PLoS Genetics (print)

JF - PLoS Genetics (print)

IS - 5

ER -