Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases
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/m2) compared to obese...
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| Format: | Online |
| Language: | English |
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Public Library of Science
2012
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364960/ |
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pubmed-3364960 |
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pubmed-33649602012-06-12 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 E. 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 Research Article 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/m2) 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 (BMI<25 kg/m2) 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. Public Library of Science 2012-05-31 /pmc/articles/PMC3364960/ /pubmed/22693455 http://dx.doi.org/10.1371/journal.pgen.1002741 Text en Perry et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
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 E. 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 |
| spellingShingle |
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 E. 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 |
| author_facet |
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 E. 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 |
| author_sort |
Perry, John R. B. |
| 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 |
| title_short |
Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases |
| title_full |
Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases |
| title_fullStr |
Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases |
| title_full_unstemmed |
Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases |
| title_sort |
stratifying type 2 diabetes cases by bmi identifies genetic risk variants in lama1 and enrichment for risk variants in lean compared to obese cases |
| description |
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/m2) 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 (BMI<25 kg/m2) 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. |
| publisher |
Public Library of Science |
| publishDate |
2012 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364960/ |
| _version_ |
1611534068693860352 |