Phenome-wide association studies demonstrating pleiotropy of genetic variants within FTO with and without adjustment for body mass index

被引：56

作者：

Cronin, Robert M. ^{[1
,2
]}

Field, Julie R. ^{[3
]}

Bradford, Yuki ^{[4
]}

Shaffer, Christian M. ^{[4
]}

Carroll, Robert J. ^{[1
]}

Mosley, Jonathan D. ^{[1
,5
]}

Bastarache, Lisa ^{[2
]}

Edwards, Todd L. ^{[6
]}

Hebbring, Scott J. ^{[7
]}

Lin, Simon ^{[8
]}

Hindorff, Lucia A. ^{[9
]}

Crane, Paul K. ^{[10
]}

Pendergrass, Sarah A. ^{[11
]}

Ritchie, Marylyn D. ^{[11
]}

Crawford, Dana C. ^{[4
]}

Pathak, Jyotishman ^{[12
,13
]}

Bielinski, Suzette J. ^{[14
]}

Carrell, David S. ^{[15
]}

Crosslin, David R. ^{[16
]}

Ledbetter, David H. ^{[17
]}

Carey, David J. ^{[18
]}

Tromp, Gerard ^{[18
]}

Williams, Marc S. ^{[17
]}

Larson, Eric B. ^{[15
]}

Jarvik, Gail P. ^{[10
,16
]}

Peissig, Peggy L. ^{[8
]}

Brilliant, Murray H. ^{[7
]}

McCarty, Catherine A. ^{[19
]}

Chute, Christopher G. ^{[12
,13
]}

Kullo, Iftikhar J. ^{[20
]}

Bottinger, Erwin ^{[21
]}

Chisholm, Rex ^{[22
]}

Smith, Maureen E. ^{[22
]}

Roden, Dan M. ^{[1
,5
]}

Denny, Joshua C. ^{[1
,2
]}

机构：

[1] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Res Off, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Ctr Human Genet Res, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA

[6] Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Nashville, TN 37232 USA

[7] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA

[8] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA

[9] NHGRI, Div Genom Med, Bethesda, MD 20892 USA

[10] Univ Washington, Dept Med, Seattle, WA USA

[11] Penn State Univ, Ctr Syst Genom, Dept Biochem & Mol Biol, University Pk, PA 16802 USA

[12] Mayo Clin, Div Biomed Informat, Rochester, MN USA

[13] Mayo Clin, Div Stat, Rochester, MN USA

[14] Mayo Clin, Div Epidemiol, Rochester, MN USA

[15] Grp Hlth Res Inst, Seattle, WA USA

[16] Univ Washington, Dept Genome Sci, Seattle, WA USA

[17] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA

[18] Geisinger Hlth Syst, Weis Ctr Res, Danville, PA USA

[19] Essentia Inst Rural Hlth, Duluth, MN USA

[20] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA

[21] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[22] Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Evanston, IL USA

来源：

FRONTIERS IN GENETICS | 2014年 / 5卷

关键词：

PheWAS; genetic association; pleiotropy; Exome chip; FTO; BMI; ELECTRONIC MEDICAL-RECORDS; EMERGE NETWORK; WAIST CIRCUMFERENCE; ASIAN POPULATIONS; DISEASE RISK; OBESITY; GENOME; GENOTYPE; IDENTIFICATION; PHEWAS;

D O I：

10.3389/fgene.2014.00250

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Phenome-wide association studies (PheWAS) have demonstrated utility in validating genetic associations derived from traditional genetic studies as well as identifying novel genetic associations. Here we used an electronic health record (EHR)-based PheWAS to explore pleiotropy of genetic variants in the fat mass and obesity associated gene (FTO), some of which have been previously associated with obesity and type 2 diabetes (T2D). We used a population of 10,487 individuals of European ancestry with genome-wide genotyping from the Electronic Medical Records and Genomics (eMERGE) Network and another population of 13,711 individuals of European ancestry from the BioVU DNA biobank at Vanderbilt genotyped using Illumina HumanExome BeadChip. A meta-analysis of the two study populations replicated the well-described associations between FTO variants and obesity (odds ratio [OR] = 1.25, 95% Confidence Interval = 1.11-1.24, p= 2.10 x 10(-9)) and FTO variants and T2D (OR= 1.14, 95% CI= 1.08-1.21, p= 2.34 x 10(-6)). The meta-analysis also demonstrated that FTO variant rs8050136 was significantly associated with sleep apnea (OR = 1.14, 95% CI = 1.07-1.22, p = 3.33 x 10(-5)); however, the association was attenuated after adjustment for body mass index (BMI). Novel phenotype associations with obesity-associated FTO variants included fibrocystic breast disease (rs9941349, OR = 0.81, 95% CI = 0.74-0.91, p = 5.41 x 10(-5)) and trends toward associations with non-alcoholic liver disease and gram-positive bacterial infections. FTO variants not associated with obesity demonstrated other potential disease associations including non-inflammatory disorders of the cervix and chronic periodontitis. These results suggest that genetic variants in FTO may have pleiotropic associations, some of which are not mediated by obesity.

引用

页数：14

共 70 条

[1] A map of human genome variation from population-scale sequencing [J].

Altshuler, David ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Collins, Francis S. ;

De la Vega, Francisco M. ;

Donnelly, Peter ;

Egholm, Michael ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Knoppers, Bartha M. ;

Lander, Eric S. ;

Lehrach, Hans ;

Mardis, Elaine R. ;

McVean, Gil A. ;

Nickerson, DebbieA. ;

Peltonen, Leena ;

Schafer, Alan J. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Deiros, David ;

Metzker, Mike ;

Muzny, Donna ;

Reid, Jeff ;

Wheeler, David ;

Wang, Jun ;

Li, Jingxiang ;

Jian, Min ;

Li, Guoqing ;

Li, Ruiqiang ;

Liang, Huiqing ;

Tian, Geng ;

Wang, Bo ;

Wang, Jian ;

Wang, Wei ;

Yang, Huanming ;

Zhang, Xiuqing ;

Zheng, Huisong ;

Lander, Eric S. ;

Altshuler, David L. ;

Ambrogio, Lauren ;

Bloom, Toby ;

Cibulskis, Kristian ;

Fennell, Tim J. ;

Gabriel, Stacey B. .

NATURE, 2010, 467 (7319) :1061-1073

[2] Early life factors and incidence of proliferative benign breast disease [J].

Baer, HJ ;

Schnitt, SJ ;

Connolly, JL ;

Byrne, C ;

Willett, WC ;

Rosner, B ;

Colditz, GA .

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 2005, 14 (12) :2889-2897

[3] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[4] Comparison of ICD-9 based, retrospective, and prospective assessments of perioperative complications assessment of accuracy in reporting Clinical article [J].

Campbell, Peter G. ;

Malone, Jennifer ;

Yadla, Sanjay ;

Chitale, Rohan ;

Nasser, Rani ;

Maltenfort, Mitchell G. ;

Vaccaro, Alex ;

Ratliff, John K. .

JOURNAL OF NEUROSURGERY-SPINE, 2011, 14 (01) :16-22

[5] R PheWAS: data analysis and plotting tools for phenome-wide association studies in the R environment [J].

Carroll, Robert J. ;

Bastarache, Lisa ;

Denny, Joshua C. .

BIOINFORMATICS, 2014, 30 (16) :2375-2376

[6] Statistical and Biological Gene-Lifestyle Interactions of MC4R and FTO with Diet and Physical Activity on Obesity: New Effects on Alcohol Consumption [J].

Corella, Dolores ;

Ortega-Azorin, Carolina ;

Sorli, Jose V. ;

Isabel Covas, M. ;

Carrasco, Paula ;

Salas-Salvado, Jordi ;

Angel Martinez-Gonzalez, Miguel ;

Aros, Fernando ;

Lapetra, Jose ;

Serra-Majem, Lluis ;

Lamuela-Raventos, Rosa ;

Gomez-Gracia, Enrique ;

Fiol, Miquel ;

Pinto, Xavier ;

Ros, Emilio ;

Marti, Amelia ;

Coltell, Oscar ;

Ordovas, Jose M. ;

Estruch, Ramon .

PLOS ONE, 2012, 7 (12)

[7] The origins and evolution of genetic disease risk in modern humans [J].

Crespi, Bernard J. .

YEAR IN EVOLUTIONARY BIOLOGY, 2010, 1206 :80-109

[8] Genetic variation associated with circulating monocyte count in the eMERGE Network [J].

Crosslin, David R. ;

McDavid, Andrew ;

Weston, Noah ;

Zheng, Xiuwen ;

Hart, Eugene ;

de Andrade, Mariza ;

Kullo, Iftikhar J. ;

McCarty, Catherine A. ;

Doheny, Kimberly F. ;

Pugh, Elizabeth ;

Kho, Abel ;

Hayes, M. Geoffrey ;

Ritchie, Marylyn D. ;

Saip, Alexander ;

Crawford, Dana C. ;

Crane, Paul K. ;

Newton, Katherine ;

Carrell, David S. ;

Gallego, Carlos J. ;

Nalls, Michael A. ;

Li, Rongling ;

Mirel, Daniel B. ;

Crenshaw, Andrew ;

Couper, David J. ;

Tanaka, Toshiko ;

van Rooij, Frank J. A. ;

Chen, Ming-Huei ;

Smith, Albert V. ;

Zakai, Neil A. ;

Yango, Qiong ;

Garcia, Melissa ;

Liu, Yongmei ;

Lumley, Thomas ;

Folsom, Aaron R. ;

Reiner, Alex P. ;

Felix, Janine F. ;

Dehghan, Abbas ;

Wilson, James G. ;

Bis, Joshua C. ;

Fox, Caroline S. ;

Glazer, Nicole L. ;

Cupples, Adrienne ;

Coresh, Josef ;

Eiriksdottir, Gudny ;

Gudnason, Vilmundur ;

Bandinelli, Stefania ;

Frayling, Timothy M. ;

Chakravarti, Aravinda ;

van Duijn, Cornelia M. ;

Melzer, David .

HUMAN MOLECULAR GENETICS, 2013, 22 (10) :2119-2127

[9] Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data [J].

Denny, Joshua C. ;

Bastarache, Lisa ;

Ritchie, Marylyn D. ;

Carroll, Robert J. ;

Zink, Raquel ;

Mosley, Jonathan D. ;

Field, Julie R. ;

Pulley, Jill M. ;

Ramirez, Andrea H. ;

Bowton, Erica ;

Basford, Melissa A. ;

Carrell, David S. ;

Peissig, Peggy L. ;

Kho, Abel N. ;

Pacheco, Jennifer A. ;

Rasmussen, Luke V. ;

Crosslin, David R. ;

Crane, Paul K. ;

Pathak, Jyotishman ;

Bielinski, Suzette J. ;

Pendergrass, Sarah A. ;

Xu, Hua ;

Hindorff, Lucia A. ;

Li, Rongling ;

Manolio, Teri A. ;

Chute, Christopher G. ;

Chisholm, Rex L. ;

Larson, Eric B. ;

Jarvik, Gail P. ;

Brilliant, Murray H. ;

McCarty, Catherine A. ;

Kullo, Iftikhar J. ;

Haines, Jonathan L. ;

Crawford, Dana C. ;

Masys, Daniel R. ;

Roden, Dan M. .

NATURE BIOTECHNOLOGY, 2013, 31 (12) :1102-+

[10] Variants Near FOXE1 Are Associated with Hypothyroidism and Other Thyroid Conditions: Using Electronic Medical Records for Genome- and Phenome-wide Studies [J].

Denny, Joshua C. ;

Crawford, Dana C. ;

Ritchie, Marylyn D. ;

Bielinski, Suzette J. ;

Basford, Melissa A. ;

Bradford, Yuki ;

Chai, High Seng ;

Bastarache, Lisa ;

Zuvich, Rebecca ;

Peissig, Peggy ;

Carrell, David ;

Ramirez, Andrea H. ;

Pathak, Jyotishman ;

Wilke, Russell A. ;

Rasmussen, Luke ;

Wang, Xiaoming ;

Pacheco, Jennifer A. ;

Kho, Abel N. ;

Hayes, M. Geoffrey ;

Weston, Noah ;

Matsumoto, Martha ;

Kopp, Peter A. ;

Newton, Katherine M. ;

Jarvik, Gail P. ;

Li, Rongling ;

Manolio, Teri A. ;

Kullo, Iftikhar J. ;

Chute, Christopher G. ;

Chisholm, Rex L. ;

Larson, Eric B. ;

McCarty, Catherine A. ;

Masys, Daniel R. ;

Roden, Dan M. ;

de Andrade, Mariza .

AMERICAN JOURNAL OF HUMAN GENETICS, 2011, 89 (04) :529-542

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