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Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile

Kilpelainen, Tuomas O.; Zillikens, M. Carola; Stancakova, Alena; Finucane, Francis M.; Ried, Janina S.; Langenberg, Claudia; Zhang, Weihua; Beckmann, Jacques S.; Luan, Jian'an and Vandenput, Liesbeth, et al. (2011) In Nature Genetics 43(8). p.58-753
Abstract
Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between similar to 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1... (More)
Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between similar to 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance. (Less)
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Nature Genetics
volume
43
issue
8
pages
58 - 753
publisher
Nature Publishing Group
external identifiers
  • wos:000293178300011
  • scopus:79960895140
ISSN
1546-1718
DOI
10.1038/ng.866
language
English
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yes
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c012bec6-2fe3-4802-80be-8e4858e52cec (old id 2071861)
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2011-09-02 08:30:10
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2017-11-19 04:02:57
@article{c012bec6-2fe3-4802-80be-8e4858e52cec,
  abstract     = {Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between similar to 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P &lt; 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.},
  author       = {Kilpelainen, Tuomas O. and Zillikens, M. Carola and Stancakova, Alena and Finucane, Francis M. and Ried, Janina S. and Langenberg, Claudia and Zhang, Weihua and Beckmann, Jacques S. and Luan, Jian'an and Vandenput, Liesbeth and Styrkarsdottir, Unnur and Zhou, Yanhua and Smith, Albert Vernon and Zhao, Jing-Hua and Amin, Najaf and Vedantam, Sailaja and Shin, So-Youn and Haritunians, Talin and Fu, Mao and Feitosa, Mary F. and Kumari, Meena and Halldorsson, Bjarni V. and Tikkanen, Emmi and Mangino, Massimo and Hayward, Caroline and Song, Ci and Arnold, Alice M. and Aulchenko, Yurii S. and Oostra, Ben A. and Campbell, Harry and Cupples, L. Adrienne and Davis, Kathryn E. and Doering, Angela and Eiriksdottir, Gudny and Estrada, Karol and Manuel Fernandez-Real, Jose and Garcia, Melissa and Gieger, Christian and Glazer, Nicole L. and Guiducci, Candace and Hofman, Albert and Humphries, Steve E. and Isomaa, Bo and Jacobs, Leonie C. and Jula, Antti and Karasik, David and Karlsson, Magnus K. and Khaw, Kay-Tee and Kim, Lauren J. and Kivimaeki, Mika and Klopp, Norman and Kuehnel, Brigitte and Kuusisto, Johanna and Liu, Yongmei and Ljunggren, Osten and Lorentzon, Mattias and Luben, Robert N. and McKnight, Barbara and Mellstrom, Dan and Mitchell, Braxton D. and Mooser, Vincent and Maria Moreno, Jose and Mannisto, Satu and O'Connell, Jeffery R. and Pascoe, Laura and Peltonen, Leena and Peral, Belen and Perola, Markus and Psaty, Bruce M. and Salomaa, Veikko and Savage, David B. and Semple, Robert K. and Skaric-Juric, Tatjana and Sigurdsson, Gunnar and Song, Kijoung S. and Spector, Timothy D. and Syvanen, Ann-Christine and Talmud, Philippa J. and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Uitterlinden, Andre G. and van Duijn, Cornelia M. and Vidal-Puig, Antonio and Wild, Sarah H. and Wright, Alan F. and Clegg, Deborah J. and Schadt, Eric and Wilson, James F. and Rudan, Igor and Ripatti, Samuli and Borecki, Ingrid B. and Shuldiner, Alan R. and Ingelsson, Erik and Jansson, John-Olov and Kaplan, Robert C. and Gudnason, Vilmundur and Harris, Tamara B. and Groop, Leif and Kiel, Douglas P. and Rivadeneira, Fernando and Walker, Mark and Barroso, Ines and Vollenweider, Peter and Waeber, Gerard and Chambers, John C. and Kooner, Jaspal S. and Soranzo, Nicole and Hirschhorn, Joel N. and Stefansson, Kari and Wichmann, H-Erich and Ohlsson, Claes and O'Rahilly, Stephen and Wareham, Nicholas J. and Speliotes, Elizabeth K. and Fox, Caroline S. and Laakso, Markku and Loos, Ruth J. F.},
  issn         = {1546-1718},
  language     = {eng},
  number       = {8},
  pages        = {58--753},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile},
  url          = {http://dx.doi.org/10.1038/ng.866},
  volume       = {43},
  year         = {2011},
}