Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively

被引：56

作者：

Wood, Andrew R. ^{[1
]}

Tyrrell, Jessica ^{[1
]}

Beaumont, Robin ^{[1
]}

Jones, Samuel E. ^{[1
]}

Tuke, Marcus A. ^{[1
]}

Ruth, Katherine S. ^{[1
]}

Yaghootkar, Hanieh ^{[1
]}

Freathy, Rachel M. ^{[1
]}

Murray, Anna ^{[1
]}

Frayling, Timothy M. ^{[1
]}

Weedon, Michael N. ^{[1
]}

机构：

[1] Univ Exeter, Sch Med, Royal Devon & Exeter Hosp, Inst Biomed & Clin Sci,Genet Complex Traits, Barrack Rd, Exeter EX2 5DW, Devon, England

来源：

DIABETOLOGIA | 2016年 / 59卷 / 06期

基金：

欧洲研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

Association analysis; BMI; CDKAL1; FTO; Genetics; Non-additive effects; Type; 2; diabetes; UK Biobank; GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; SUSCEPTIBILITY LOCI; INSIGHTS;

D O I：

10.1007/s00125-016-3908-5

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims/hypothesis Genome-wide association (GWA) studies have identified hundreds of common genetic variants associated with obesity and type 2 diabetes. These studies have usually focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases. Methods We performed a GWA study using a dominance deviation model for BMI, obesity (29,925 cases) and type 2 diabetes (4,040 cases) in 120,286 individuals of British ancestry from the UK Biobank study. We also investigated whether single nucleotide polymorphisms previously shown to be associated with these traits showed any enrichment for departures from additivity. Results Known obesity-associated variants in FTO showed strong evidence of deviation from additivity (p(DOMDEV) = 3 x 10(-5)) through a recessive effect of the allele associated with higher BMI. The average BMI of individuals carrying zero, one or two BMI-raising alleles was 27.27 (95% CI 27.22, 27.31) kg/m(2), 27.54 (95% CI 27.50, 27.58) kg/m(2) and 28.07 (95% CI 28.00, 28.14) kg/m(2), respectively. A similar effect was observed in 105,643 individuals from the GIANT Consortium (p(DOMDEV) = 0.003; meta-analysis p(DOMDEV) = 1 x 10(-7)). For type 2 diabetes, we detected a recessive effect (p(DOMDEV) = 5 x 10(-4)) at CDKAL1. Relative to homozygous non-risk allele carriers, homozygous risk allele carriers had an OR of 1.48 (95% CI 1.32, 1.65), while the heterozygous group had an OR of 1.06 (95% CI 0.99, 1.14), a result consistent with that of a previous study. We did not identify any novel associations at genome-wide significance. Conclusions/interpretation Although we found no evidence of widespread non-additive genetic effects contributing to obesity and type 2 diabetes risk, we did find robust examples of recessive effects at the FTO and CDKAL1 loci. Access to research materials Summary statistics are available at www.t2diabetesgenes.org and by request (a.r.wood@exeter.ac.uk). All underlying data are available on application from the UK Biobank.

引用

页码：1214 / 1221

页数：8

共 22 条

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Freathy, Rachel M. ;

Lindgren, Cecilia M. ;

Perry, John R. B. ;

Elliott, Katherine S. ;

Lango, Hana ;

Rayner, Nigel W. ;

Shields, Beverley ;

Harries, Lorna W. ;

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Elder, James T. ;

Gregersen, Peter K. ;

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Go, Min Jin ;

Zhang, Weihua ;

Below, Jennifer E. ;

Gaulton, Kyle J. ;

Ferreira, Teresa ;

Horikoshi, Momoko ;

Johnson, Andrew D. ;

Ng, Maggie C. Y. ;

Prokopenko, Inga ;

Saleheen, Danish ;

Wang, Xu ;

Zeggini, Eleftheria ;

Abecasis, Goncalo R. ;

Adair, Linda S. ;

Almgren, Peter ;

Atalay, Mustafa ;

Aung, Tin ;

Baldassarre, Damiano ;

Balkau, Beverley ;

Bao, Yuqian ;

Barnett, Anthony H. ;

Barroso, Ines ;

Basit, Abdul ;

Been, Latonya F. ;

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Bell, Graeme I. ;

Benediktsson, Rafn ;

Bergman, Richard N. ;

Boehm, Bernhard O. ;

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McCarthy, Mark I. ;

Abecasis, Goncalo R. ;

Cardon, Lon R. ;

Goldstein, David B. ;

Little, Julian ;

Ioannidis, John P. A. ;

Hirschhorn, Joel N. .

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Morris, Andrew P. ;

Voight, Benjamin F. ;

Teslovich, Tanya M. ;

Ferreira, Teresa ;

Segre, Ayellet V. ;

Steinthorsdottir, Valgerdur ;

Strawbridge, Rona J. ;

Khan, Hassan ;

Grallert, Harald ;

Mahajan, Anubha ;

Prokopenko, Inga ;

Kang, Hyun Min ;

Dina, Christian ;

Esko, Tonu ;

Fraser, Ross M. ;

Kanoni, Stavroula ;

Kumar, Ashish ;

Lagou, Vasiliki ;

Langenberg, Claudia ;

Luan, Jian'an ;

Lindgren, Cecilia M. ;

Mueller-Nurasyid, Martina ;

Pechlivanis, Sonali ;

Rayner, N. William ;

Scott, Laura J. ;

Wiltshire, Steven ;

Yengo, Loic ;

Kinnunen, Leena ;

Rossin, Elizabeth J. ;

Raychaudhuri, Soumya ;

Johnson, Andrew D. ;

Dimas, Antigone S. ;

Loos, Ruth J. F. ;

Vedantam, Sailaja ;

Chen, Han ;

Florez, Jose C. ;

Fox, Caroline ;

Liu, Ching-Ti ;

Rybin, Denis ;

Couper, David J. ;

Kao, Wen Hong L. ;

Li, Man ;

Cornelis, Marilyn C. ;

Kraft, Peter ;

Sun, Qi ;

van Dam, Rob M. ;

Stringham, Heather M. ;

Chines, Peter S. ;

Fischer, Krista ;

Fontanillas, Pierre .

NATURE GENETICS, 2012, 44 (09) :981-+

← 1 2 3 →

共 22 条

[1] Fast Principal Component Analysis of Large-Scale Genome-Wide Data [J].

Abraham, Gad ;

Inouye, Michael .

PLOS ONE, 2014, 9 (04)

[2] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[3] FTO Obesity Variant Circuitry and Adipocyte Browning in Humans [J].

Claussnitzer, Melina ;

Dankel, Simon N. ;

Kim, Kyoung-Han ;

Quon, Gerald ;

Meuleman, Wouter ;

Haugen, Christine ;

Glunk, Viktoria ;

Sousa, Isabel S. ;

Beaudry, Jacqueline L. ;

Puviindran, Vijitha ;

Abdennur, Nezar A. ;

Liu, Jannel ;

Svensson, Per-Arne ;

Hsu, Yi-Hsiang ;

Drucker, Daniel J. ;

Mellgren, Gunnar ;

Hui, Chi-Chung ;

Hauner, Hans ;

Kellis, Manolis .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (10) :895-907

[4] A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity [J].

Frayling, Timothy M. ;

Timpson, Nicholas J. ;

Weedon, Michael N. ;

Zeggini, Eleftheria ;

Freathy, Rachel M. ;

Lindgren, Cecilia M. ;

Perry, John R. B. ;

Elliott, Katherine S. ;

Lango, Hana ;

Rayner, Nigel W. ;

Shields, Beverley ;

Harries, Lorna W. ;

Barrett, Jeffrey C. ;

Ellard, Sian ;

Groves, Christopher J. ;

Knight, Bridget ;

Patch, Ann-Marie ;

Ness, Andrew R. ;

Ebrahim, Shah ;

Lawlor, Debbie A. ;

Ring, Susan M. ;

Ben-Shlomo, Yoav ;

Jarvelin, Marjo-Riitta ;

Sovio, Ulla ;

Bennett, Amanda J. ;

Melzer, David ;

Ferrucci, Luigi ;

Loos, Ruth J. F. ;

Barroso, Ines ;

Wareham, Nicholas J. ;

Karpe, Fredrik ;

Owen, Katharine R. ;

Cardon, Lon R. ;

Walker, Mark ;

Hitman, Graham A. ;

Palmer, Colin N. A. ;

Doney, Alex S. F. ;

Morris, Andrew D. ;

Smith, George Davey ;

Hattersley, Andrew T. ;

McCarthy, Mark I. .

SCIENCE, 2007, 316 (5826) :889-894

[5]

Gauderman W.J., 2006, QUANTO 1.1 A Computer Program for Power and Sample Size Calculations for Genetic-Epidemiology Studies

[6] Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases [J].

Lenz, Tobias L. ;

Deutsch, Aaron J. ;

Han, Buhm ;

Hu, Xinli ;

Okada, Yukinori ;

Eyre, Stephen ;

Knapp, Michael ;

Zhernakova, Alexandra ;

Huizinga, Tom W. J. ;

Abecasis, Goncalo ;

Becker, Jessica ;

Boeckxstaens, Guy E. ;

Chen, Wei-Min ;

Franke, Andre ;

Gladman, Dafna D. ;

Gockel, Ines ;

Gutierrez-Achury, Javier ;

Martin, Javier ;

Nair, Rajan P. ;

Noethen, Markus M. ;

Onengut-Gumuscu, Suna ;

Rahman, Proton ;

Rantapaa-Dahlqvist, Solbritt ;

Stuart, Philip E. ;

Tsoi, Lam C. ;

van Heel, David A. ;

Worthington, Jane ;

Wouters, Mira M. ;

Klareskog, Lars ;

Elder, James T. ;

Gregersen, Peter K. ;

Schumacher, Johannes ;

Rich, Stephen S. ;

Wijmenga, Cisca ;

Sunyaev, Shamil R. ;

de Bakker, Paul I. W. ;

Raychaudhuri, Soumya .

NATURE GENETICS, 2015, 47 (09) :1085-+

[7] Genetic studies of body mass index yield new insights for obesity biology [J].

Locke, Adam E. ;

Kahali, Bratati ;

Berndt, Sonja I. ;

Justice, Anne E. ;

Pers, Tune H. ;

Day, Felix R. ;

Powell, Corey ;

Vedantam, Sailaja ;

Buchkovich, Martin L. ;

Yang, Jian ;

Croteau-Chonka, Damien C. ;

Esko, Tonu ;

Fall, Tove ;

Ferreira, Teresa ;

Gustafsson, Stefan ;

Kutalik, Zoltan ;

Luan, Jian'an ;

Maegi, Reedik ;

Randall, Joshua C. ;

Winkler, Thomas W. ;

Wood, Andrew R. ;

Workalemahu, Tsegaselassie ;

Faul, Jessica D. ;

Smith, Jennifer A. ;

Zhao, Jing Hua ;

Zhao, Wei ;

Chen, Jin ;

Fehrmann, Rudolf ;

Hedman, Asa K. ;

Karjalainen, Juha ;

Schmidt, Ellen M. ;

Absher, Devin ;

Amin, Najaf ;

Anderson, Denise ;

Beekman, Marian ;

Bolton, Jennifer L. ;

Bragg-Gresham, L. ;

Buyske, Steven ;

Demirkan, Ayse ;

Deng, Guohong ;

Ehret, Georg B. ;

Feenstra, Bjarke ;

Feitosa, Mary F. ;

Fischer, Krista ;

Goel, Anuj ;

Gong, Jian ;

Jackson, Anne U. ;

Kanoni, Stavroula ;

Kleber, Marcus E. ;

Kristiansson, Kati .

NATURE, 2015, 518 (7538) :197-+

[8] Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility [J].

Mahajan, Anubha ;

Go, Min Jin ;

Zhang, Weihua ;

Below, Jennifer E. ;

Gaulton, Kyle J. ;

Ferreira, Teresa ;

Horikoshi, Momoko ;

Johnson, Andrew D. ;

Ng, Maggie C. Y. ;

Prokopenko, Inga ;

Saleheen, Danish ;

Wang, Xu ;

Zeggini, Eleftheria ;

Abecasis, Goncalo R. ;

Adair, Linda S. ;

Almgren, Peter ;

Atalay, Mustafa ;

Aung, Tin ;

Baldassarre, Damiano ;

Balkau, Beverley ;

Bao, Yuqian ;

Barnett, Anthony H. ;

Barroso, Ines ;

Basit, Abdul ;

Been, Latonya F. ;

Beilby, John ;

Bell, Graeme I. ;

Benediktsson, Rafn ;

Bergman, Richard N. ;

Boehm, Bernhard O. ;

Boerwinkle, Eric ;

Bonnycastle, Lori L. ;

Burtt, Noel ;

Cai, Qiuyin ;

Campbell, Harry ;

Carey, Jason ;

Cauchi, Stephane ;

Caulfield, Mark ;

Chan, Juliana C. N. ;

Chang, Li-Ching ;

Chang, Tien-Jyun ;

Chang, Yi-Cheng ;

Charpentier, Guillaume ;

Chen, Chien-Hsiun ;

Chen, Han ;

Chen, Yuan-Tsong ;

Chia, Kee-Seng ;

Chidambaram, Manickam ;

Chines, Peter S. ;

Cho, Nam H. .

NATURE GENETICS, 2014, 46 (03) :234-+

[9] Genome-wide association studies for complex traits: consensus, uncertainty and challenges [J].

McCarthy, Mark I. ;

Abecasis, Goncalo R. ;

Cardon, Lon R. ;

Goldstein, David B. ;

Little, Julian ;

Ioannidis, John P. A. ;

Hirschhorn, Joel N. .

NATURE REVIEWS GENETICS, 2008, 9 (05) :356-369

[10] Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes [J].

Morris, Andrew P. ;

Voight, Benjamin F. ;

Teslovich, Tanya M. ;

Ferreira, Teresa ;

Segre, Ayellet V. ;

Steinthorsdottir, Valgerdur ;

Strawbridge, Rona J. ;

Khan, Hassan ;

Grallert, Harald ;

Mahajan, Anubha ;

Prokopenko, Inga ;

Kang, Hyun Min ;

Dina, Christian ;

Esko, Tonu ;

Fraser, Ross M. ;

Kanoni, Stavroula ;

Kumar, Ashish ;

Lagou, Vasiliki ;

Langenberg, Claudia ;

Luan, Jian'an ;

Lindgren, Cecilia M. ;

Mueller-Nurasyid, Martina ;

Pechlivanis, Sonali ;

Rayner, N. William ;

Scott, Laura J. ;

Wiltshire, Steven ;

Yengo, Loic ;

Kinnunen, Leena ;

Rossin, Elizabeth J. ;

Raychaudhuri, Soumya ;

Johnson, Andrew D. ;

Dimas, Antigone S. ;

Loos, Ruth J. F. ;

Vedantam, Sailaja ;

Chen, Han ;

Florez, Jose C. ;

Fox, Caroline ;

Liu, Ching-Ti ;

Rybin, Denis ;

Couper, David J. ;

Kao, Wen Hong L. ;

Li, Man ;

Cornelis, Marilyn C. ;

Kraft, Peter ;

Sun, Qi ;

van Dam, Rob M. ;

Stringham, Heather M. ;

Chines, Peter S. ;

Fischer, Krista ;

Fontanillas, Pierre .

NATURE GENETICS, 2012, 44 (09) :981-+

← 1 2 3 →