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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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",

issn = "1553-7390",

publisher = "Public Library of Science",

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, 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

VL - 8

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 5

ER -