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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2012
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oai:doaj.org-article:69278706f1ba4c3e8b31e43c60a600aa2021-11-18T06:18:31ZStratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.1553-73901553-740410.1371/journal.pgen.1002741https://doaj.org/article/69278706f1ba4c3e8b31e43c60a600aa2012-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22693455/pdf/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Common 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.John R B PerryBenjamin F VoightLoïc YengoNajaf AminJosée DupuisMartha GanserHarald GrallertPau NavarroMan LiLu QiValgerdur SteinthorsdottirRobert A ScottPeter AlmgrenDan E ArkingYurii AulchenkoBeverley BalkauRafn BenediktssonRichard N BergmanEric BoerwinkleLori BonnycastleNoël P BurttHarry CampbellGuillaume CharpentierFrancis S CollinsChristian GiegerTodd GreenSamy HadjadjAndrew T HattersleyChristian HerderAlbert HofmanAndrew D JohnsonAnna KottgenPeter KraftYann LabruneClaudia LangenbergAlisa K ManningKaren L MohlkeAndrew P MorrisBen OostraJames PankowAnn-Kristin PetersenPeter P PramstallerInga ProkopenkoWolfgang RathmannWilliam RaynerMichael RodenIgor RudanDenis RybinLaura J ScottGunnar SigurdssonRob SladekGudmar ThorleifssonUnnur ThorsteinsdottirJaakko TuomilehtoAndre G UitterlindenSidonie VivequinMichael N WeedonAlan F WrightMAGICDIAGRAM ConsortiumGIANT ConsortiumFrank B HuThomas IlligLinda KaoJames B MeigsJames F WilsonKari StefanssonCornelia van DuijnDavid AltschulerAndrew D MorrisMichael BoehnkeMark I McCarthyPhilippe FroguelColin N A PalmerNicholas J WarehamLeif GroopTimothy M FraylingStéphane CauchiPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 8, Iss 5, p e1002741 (2012) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 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 E Arking Yurii Aulchenko Beverley Balkau Rafn Benediktsson Richard N Bergman Eric Boerwinkle Lori Bonnycastle Noël 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 MAGIC DIAGRAM Consortium GIANT Consortium 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 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. |
| format |
article |
| author |
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 E Arking Yurii Aulchenko Beverley Balkau Rafn Benediktsson Richard N Bergman Eric Boerwinkle Lori Bonnycastle Noël 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 MAGIC DIAGRAM Consortium GIANT Consortium 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 |
| author_facet |
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 E Arking Yurii Aulchenko Beverley Balkau Rafn Benediktsson Richard N Bergman Eric Boerwinkle Lori Bonnycastle Noël 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 MAGIC DIAGRAM Consortium GIANT Consortium 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 |
| author_sort |
John R B Perry |
| 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. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/69278706f1ba4c3e8b31e43c60a600aa |
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