Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?
The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies wit...
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2009-10-01
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| Series: | PLoS Genetics |
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| author | Iris M Heid Cornelia Huth Ruth J F Loos Florian Kronenberg Vera Adamkova Sonia S Anand Kristin Ardlie Heike Biebermann Peter Bjerregaard Heiner Boeing Claude Bouchard Marina Ciullo Jackie A Cooper Dolores Corella Christian Dina James C Engert Eva Fisher Francesc Francès Philippe Froguel Johannes Hebebrand Robert A Hegele Anke Hinney Margret R Hoehe Frank B Hu Jaroslav A Hubacek Steve E Humphries Steven C Hunt Thomas Illig Marjo-Riita Järvelin Marika Kaakinen Barbara Kollerits Heiko Krude Jitender Kumar Leslie A Lange Birgit Langer Shengxu Li Andreas Luchner Helen N Lyon David Meyre Karen L Mohlke Vincent Mooser Almut Nebel Thuy Trang Nguyen Bernhard Paulweber Louis Perusse Lu Qi Tuomo Rankinen Dieter Rosskopf Stefan Schreiber Shantanu Sengupta Rossella Sorice Anita Suk Gudmar Thorleifsson Unnur Thorsteinsdottir Henry Völzke Karani S Vimaleswaran Nicholas J Wareham Dawn Waterworth Salim Yusuf Cecilia Lindgren Mark I McCarthy Christoph Lange Joel N Hirschhorn Nan Laird H-Erich Wichmann |
| author_facet | Iris M Heid Cornelia Huth Ruth J F Loos Florian Kronenberg Vera Adamkova Sonia S Anand Kristin Ardlie Heike Biebermann Peter Bjerregaard Heiner Boeing Claude Bouchard Marina Ciullo Jackie A Cooper Dolores Corella Christian Dina James C Engert Eva Fisher Francesc Francès Philippe Froguel Johannes Hebebrand Robert A Hegele Anke Hinney Margret R Hoehe Frank B Hu Jaroslav A Hubacek Steve E Humphries Steven C Hunt Thomas Illig Marjo-Riita Järvelin Marika Kaakinen Barbara Kollerits Heiko Krude Jitender Kumar Leslie A Lange Birgit Langer Shengxu Li Andreas Luchner Helen N Lyon David Meyre Karen L Mohlke Vincent Mooser Almut Nebel Thuy Trang Nguyen Bernhard Paulweber Louis Perusse Lu Qi Tuomo Rankinen Dieter Rosskopf Stefan Schreiber Shantanu Sengupta Rossella Sorice Anita Suk Gudmar Thorleifsson Unnur Thorsteinsdottir Henry Völzke Karani S Vimaleswaran Nicholas J Wareham Dawn Waterworth Salim Yusuf Cecilia Lindgren Mark I McCarthy Christoph Lange Joel N Hirschhorn Nan Laird H-Erich Wichmann |
| author_sort | Iris M Heid |
| collection | DOAJ |
| description | The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I(2) measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2) measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI> or =32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI<25 kg/m(2)) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far. |
| format | Article |
| id | doaj-art-48b5ddba957d4effaae19a30092a0bee |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2009-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-48b5ddba957d4effaae19a30092a0bee2025-08-20T03:19:53ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042009-10-01510e100069410.1371/journal.pgen.1000694Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?Iris M HeidCornelia HuthRuth J F LoosFlorian KronenbergVera AdamkovaSonia S AnandKristin ArdlieHeike BiebermannPeter BjerregaardHeiner BoeingClaude BouchardMarina CiulloJackie A CooperDolores CorellaChristian DinaJames C EngertEva FisherFrancesc FrancèsPhilippe FroguelJohannes HebebrandRobert A HegeleAnke HinneyMargret R HoeheFrank B HuJaroslav A HubacekSteve E HumphriesSteven C HuntThomas IlligMarjo-Riita JärvelinMarika KaakinenBarbara KolleritsHeiko KrudeJitender KumarLeslie A LangeBirgit LangerShengxu LiAndreas LuchnerHelen N LyonDavid MeyreKaren L MohlkeVincent MooserAlmut NebelThuy Trang NguyenBernhard PaulweberLouis PerusseLu QiTuomo RankinenDieter RosskopfStefan SchreiberShantanu SenguptaRossella SoriceAnita SukGudmar ThorleifssonUnnur ThorsteinsdottirHenry VölzkeKarani S VimaleswaranNicholas J WarehamDawn WaterworthSalim YusufCecilia LindgrenMark I McCarthyChristoph LangeJoel N HirschhornNan LairdH-Erich WichmannThe INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I(2) measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2) measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI> or =32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI<25 kg/m(2)) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000694&type=printable |
| spellingShingle | Iris M Heid Cornelia Huth Ruth J F Loos Florian Kronenberg Vera Adamkova Sonia S Anand Kristin Ardlie Heike Biebermann Peter Bjerregaard Heiner Boeing Claude Bouchard Marina Ciullo Jackie A Cooper Dolores Corella Christian Dina James C Engert Eva Fisher Francesc Francès Philippe Froguel Johannes Hebebrand Robert A Hegele Anke Hinney Margret R Hoehe Frank B Hu Jaroslav A Hubacek Steve E Humphries Steven C Hunt Thomas Illig Marjo-Riita Järvelin Marika Kaakinen Barbara Kollerits Heiko Krude Jitender Kumar Leslie A Lange Birgit Langer Shengxu Li Andreas Luchner Helen N Lyon David Meyre Karen L Mohlke Vincent Mooser Almut Nebel Thuy Trang Nguyen Bernhard Paulweber Louis Perusse Lu Qi Tuomo Rankinen Dieter Rosskopf Stefan Schreiber Shantanu Sengupta Rossella Sorice Anita Suk Gudmar Thorleifsson Unnur Thorsteinsdottir Henry Völzke Karani S Vimaleswaran Nicholas J Wareham Dawn Waterworth Salim Yusuf Cecilia Lindgren Mark I McCarthy Christoph Lange Joel N Hirschhorn Nan Laird H-Erich Wichmann Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design? PLoS Genetics |
| title | Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design? |
| title_full | Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design? |
| title_fullStr | Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design? |
| title_full_unstemmed | Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design? |
| title_short | Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design? |
| title_sort | meta analysis of the insig2 association with obesity including 74 345 individuals does heterogeneity of estimates relate to study design |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000694&type=printable |
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