title: Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake.
abstract: BACKGROUND
  Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
  
  
  OBJECTIVE
  The objective of the study was to identify common genetic variants that are associated with macronutrient intake.
  
  
  METHODS
  We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.
  
  
  RESULTS
  A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)).
  
  
  CONCLUSIONS
  Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
authors: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21225, USA. tanakato@mail.nih.gov
authors: Toshiko
authors: T
authors: Tanaka
authors: Julius S
authors: JS
authors: Ngwa
authors: Frank J A
authors: FJ
authors: van Rooij
authors: M Carola
authors: MC
authors: Zillikens
authors: Mary K
authors: MK
authors: Wojczynski
authors: Alexis C
authors: AC
authors: Frazier-Wood
authors: Denise K
authors: DK
authors: Houston
authors: Stavroula
authors: S
authors: Kanoni
authors: Rozenn N
authors: RN
authors: Lemaitre
authors: Jian'an
authors: J
authors: Luan
authors: Vera
authors: V
authors: Mikkilä
authors: Frida
authors: F
authors: Renstrom
authors: Emily
authors: E
authors: Sonestedt
authors: Jing Hua
authors: JH
authors: Zhao
authors: Audrey Y
authors: AY
authors: Chu
authors: Lu
authors: L
authors: Qi
authors: Daniel I
authors: DI
authors: Chasman
authors: Marcia C
authors: MC
authors: de Oliveira Otto
authors: Emily J
authors: EJ
authors: Dhurandhar
authors: Mary F
authors: MF
authors: Feitosa
authors: Ingegerd
authors: I
authors: Johansson
authors: Kay-Tee
authors: KT
authors: Khaw
authors: Kurt K
authors: KK
authors: Lohman
authors: Ani
authors: A
authors: Manichaikul
authors: Nicola M
authors: NM
authors: McKeown
authors: Dariush
authors: D
authors: Mozaffarian
authors: Andrew
authors: A
authors: Singleton
authors: Kathleen
authors: K
authors: Stirrups
authors: Jorma
authors: J
authors: Viikari
authors: Zheng
authors: Z
authors: Ye
authors: Stefania
authors: S
authors: Bandinelli
authors: Inês
authors: I
authors: Barroso
authors: Panos
authors: P
authors: Deloukas
authors: Nita G
authors: NG
authors: Forouhi
authors: Albert
authors: A
authors: Hofman
authors: Yongmei
authors: Y
authors: Liu
authors: Leo-Pekka
authors: LP
authors: Lyytikäinen
authors: Kari E
authors: KE
authors: North
authors: Maria
authors: M
authors: Dimitriou
authors: Goran
authors: G
authors: Hallmans
authors: Mika
authors: M
authors: Kähönen
authors: Claudia
authors: C
authors: Langenberg
authors: Jose M
authors: JM
authors: Ordovas
authors: André G
authors: AG
authors: Uitterlinden
authors: Frank B
authors: FB
authors: Hu
authors: Ioanna-Panagiota
authors: IP
authors: Kalafati
authors: Olli
authors: O
authors: Raitakari
authors: Oscar H
authors: OH
authors: Franco
authors: Andrew
authors: A
authors: Johnson
authors: Valur
authors: V
authors: Emilsson
authors: Jennifer A
authors: JA
authors: Schrack
authors: Richard D
authors: RD
authors: Semba
authors: David S
authors: DS
authors: Siscovick
authors: Donna K
authors: DK
authors: Arnett
authors: Ingrid B
authors: IB
authors: Borecki
authors: Paul W
authors: PW
authors: Franks
authors: Stephen B
authors: SB
authors: Kritchevsky
authors: Terho
authors: T
authors: Lehtimäki
authors: Ruth J F
authors: RJ
authors: Loos
authors: Marju
authors: M
authors: Orho-Melander
authors: Jerome I
authors: JI
authors: Rotter
authors: Nicholas J
authors: NJ
authors: Wareham
authors: Jacqueline C M
authors: JC
authors: Witteman
authors: Luigi
authors: L
authors: Ferrucci
authors: George
authors: G
authors: Dedoussis
authors: L Adrienne
authors: LA
authors: Cupples
authors: Jennifer A
authors: JA
authors: Nettleton
mesh_terms: D000483:Alleles; D050197:Atherosclerosis / Q000235:genetics; D015992:Body Mass Index; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D004041:Dietary Fats / Q000008:administration & dosage*; D004044:Dietary Proteins / Q000008:administration & dosage*; D002149:Energy Intake; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics; D005500:Follow-Up Studies; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008019:Life Style; D009765:Obesity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D040641:Quantitative Trait Loci; D011795:Surveys and Questionnaires; D044465:White People / Q000235:genetics
chemical_list: D004040:Dietary Carbohydrates; D004041:Dietary Fats; D004044:Dietary Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
references: Am J Clin Nutr. 2011 Apr;93(4):901S-5
references: 21346090
references: Clin Chem. 2008 Feb;54(2):249-55
references: 18070814
references: Exp Clin Endocrinol Diabetes. 2009 Apr;117(4):194-7
references: 19053021
references: Am J Hum Genet. 2006 Apr;78(4):629-44
references: 16532393
references: Obesity (Silver Spring). 2008 Aug;16(8):1961-5
references: 18551109
references: Bioinformatics. 2010 Sep 1;26(17):2190-1
references: 20616382
references: Nat Genet. 2007 Jun;39(6):724-6
references: 17496892
references: Diabetes. 2008 May;57(5):1246-53
references: 18252893
references: Genome Res. 2011 Jul;21(7):1008-16
references: 21602305
references: Nature. 2008 Mar 27;452(7186):423-8
references: 18344981
references: Hum Mol Genet. 2013 May 1;22(9):1895-902
references: 23372041
references: Am J Clin Nutr. 2008 Oct;88(4):971-8
references: 18842783
references: Endocrinology. 2007 Feb;148(2):774-81
references: 17068132
references: Am J Clin Nutr. 2005 Aug;82(2):467-70
references: 16087994
references: PLoS Genet. 2007 Jul;3(7):e115
references: 17658951
references: N Engl J Med. 2008 Dec 11;359(24):2558-66
references: 19073975
references: Am J Clin Nutr. 2010 Jan;91(1):254S-257S
references: 19906798
references: Science. 2007 May 11;316(5826):889-94
references: 17434869
references: Am J Clin Nutr. 2009 Oct;90(4):951-9
references: 19692490
references: Am J Clin Nutr. 2004 May;79(5):881-6
references: 15113729
references: Cell Metab. 2007 Jun;5(6):415-25
references: 17550777
references: J Nutrigenet Nutrigenomics. 2009;2(4-5):235-42
references: 20357494
references: Lancet. 1991 Aug 24;338(8765):464-8
references: 1678444
references: Diabetes. 2011 Nov;60(11):2758-62
references: 21926274
references: Am J Clin Nutr. 2009 Nov;90(5):1418-25
references: 19726594
references: Hum Mol Genet. 2008 Nov 15;17(22):3502-8
references: 18697794
references: Am J Clin Nutr. 2008 Oct;88(4):1142-8
references: 18842805
references: Diabetes Care. 2010 Dec;33(12):2684-91
references: 20693352
references: PLoS Genet. 2011 Jun;7(6):e1002113
references: 21738480
references: Am J Clin Nutr. 2004 Nov;80(5):1410-4
references: 15531694
references: Cell Metab. 2008 Aug;8(2):169-74
references: 18680716
references: Obesity (Silver Spring). 2006 Sep;14(9):1596-604
references: 17030971
references: Nat Genet. 2010 Jan;42(1):62-7
references: 19966804
references: Nat Rev Cancer. 2005 May;5(5):388-96
references: 15864280
references: Nat Genet. 2007 Oct;39(10):1208-16
references: 17873875
references: Cell Metab. 2007 Jun;5(6):426-37
references: 17550778
references: PLoS Genet. 2011 May;7(5):e1002078
references: 21637794
references: J Clin Invest. 2005 Jun;115(6):1627-35
references: 15902306
references: PLoS Genet. 2011 Aug;7(8):e1002197
references: 21829388
references: Diabetes. 2010 Jul;59(7):1817-24
references: 20357365
references: J Nutr. 2010 Apr;140(4):831-4
references: 20181787
references: Int J Obes Relat Metab Disord. 2000 Jul;24(7):920-4
references: 10918541
references: Nat Genet. 2007 Jul;39(7):906-13
references: 17572673
references: Diabetes. 2010 Nov;59(11):2781-9
references: 20682689
references: PLoS Biol. 2008 May 6;6(5):e107
references: 18462017
references: Annu Rev Nutr. 2006;26:413-34
references: 16848714
references: BMC Neurosci. 2009 Oct 27;10:129
references: 19860904
references: Am J Clin Nutr. 2004 Jul;80(1):82-8
references: 15213032