Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake

Toshiko Tanaka; Julius S. Ngwa; Frank J.A. Van Rooij; M. Carola Zillikens; Mary K. Wojczynski; Alexis C. Frazier-Wood; Denise K. Houston; Stavroula Kanoni; Rozenn N. Lemaitre; Jia N.An Luan; Vera Mikkilä; Frida Renstrom; Emily Sonestedt; Jing Hua Zhao; Audrey Y. Chu; Lu Qi; Daniel I. Chasman; Marcia C. De Oliveira Otto; Emily J. Dhurandhar; Mary F. Feitosa; Ingegerd Johansson; Kay Tee Khaw; Kurt K. Lohman; Ani Manichaikul; Nicola M. McKeown; Dariush Mozaffarian; Andrew Singleton; Kathleen Stirrups; Jorma Viikari; Zheng Ye; Stefania Bandinelli; Inês Barroso; Panos Deloukas; Nita G. Forouhi; Albert Hofman; Yongmei Liu; Leo Pekka Lyytikäinen; Kari E. North; Maria Dimitriou; Goran Hallmans; Mika Kähönen; Claudia Langenberg; Jose M. Ordovas; André G. Uitterlinden; Frank B. Hu; Ioanna Panagiota Kalafati; Olli Raitakari; Oscar H. Franco; Andrew Johnson; Valur Emilsson; Jennifer A. Schrack; Richard D. Semba; David S. Siscovick; Donna K. Arnett; Ingrid B. Borecki; Paul W. Franks; Stephen B. Kritchevsky; Terho Lehtimäki Ruth J.F. Loos; Marju Orho-Melander; Jerome I. Rotter; Nicholas J. Wareham; Jacqueline C.M. Witteman; Luigi Ferrucci; George Dedoussis; L. Adrienne Cupples; Jennifer A. Nettleton

doi:10.3945/ajcn.112.052183

Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake

Toshiko Tanaka, Julius S. Ngwa, Frank J.A. Van Rooij, M. Carola Zillikens, Mary K. Wojczynski, Alexis C. Frazier-Wood, Denise K. Houston, Stavroula Kanoni, Rozenn N. Lemaitre, Jia N.An Luan, Vera Mikkilä, Frida Renstrom, Emily Sonestedt, Jing Hua Zhao, Audrey Y. Chu, Lu Qi, Daniel I. Chasman, Marcia C. De Oliveira Otto, Emily J. Dhurandhar, Mary F. FeitosaIngegerd Johansson, Kay Tee Khaw, Kurt K. Lohman, Ani Manichaikul, Nicola M. McKeown, Dariush Mozaffarian, Andrew Singleton, Kathleen Stirrups, Jorma Viikari, Zheng Ye, Stefania Bandinelli, Inês Barroso, Panos Deloukas, Nita G. Forouhi, Albert Hofman, Yongmei Liu, Leo Pekka Lyytikäinen, Kari E. North, Maria Dimitriou, Goran Hallmans, Mika Kähönen, Claudia Langenberg, Jose M. Ordovas, André G. Uitterlinden, Frank B. Hu, Ioanna Panagiota Kalafati, Olli Raitakari, Oscar H. Franco, Andrew Johnson, Valur Emilsson, Jennifer A. Schrack, Richard D. Semba, David S. Siscovick, Donna K. Arnett, Ingrid B. Borecki, Paul W. Franks, Stephen B. Kritchevsky, Terho Lehtimäki Ruth J.F. Loos, Marju Orho-Melander, Jerome I. Rotter, Nicholas J. Wareham, Jacqueline C.M. Witteman, Luigi Ferrucci, George Dedoussis, L. Adrienne Cupples, Jennifer A. Nettleton

Department of Genetics

Research output: Contribution to journal › Article › peer-review

186 Scopus citations

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. Design: 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). Conclusion: 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).

Original language	English
Pages (from-to)	1395-1402
Number of pages	8
Journal	American Journal of Clinical Nutrition
Volume	97
Issue number	6
DOIs	https://doi.org/10.3945/ajcn.112.052183
State	Published - Jun 1 2013

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Tanaka, T., Ngwa, J. S., Van Rooij, F. J. A., Zillikens, M. C., Wojczynski, M. K., Frazier-Wood, A. C., Houston, D. K., Kanoni, S., Lemaitre, R. N., Luan, J. N. A., Mikkilä, V., Renstrom, F., Sonestedt, E., Zhao, J. H., Chu, A. Y., Qi, L., Chasman, D. I., De Oliveira Otto, M. C., Dhurandhar, E. J., ... Nettleton, J. A. (2013). Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. American Journal of Clinical Nutrition, 97(6), 1395-1402. https://doi.org/10.3945/ajcn.112.052183

@article{9b9eb75e9f8640d1907ff3cbac6c3216,

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. Design: 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). Conclusion: 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).",

author = "Toshiko Tanaka and Ngwa, {Julius S.} and {Van Rooij}, {Frank J.A.} and Zillikens, {M. Carola} and Wojczynski, {Mary K.} and Frazier-Wood, {Alexis C.} and Houston, {Denise K.} and Stavroula Kanoni and Lemaitre, {Rozenn N.} and Luan, {Jia N.An} and Vera Mikkil{\"a} and Frida Renstrom and Emily Sonestedt and Zhao, {Jing Hua} and Chu, {Audrey Y.} and Lu Qi and Chasman, {Daniel I.} and {De Oliveira Otto}, {Marcia C.} and Dhurandhar, {Emily J.} and Feitosa, {Mary F.} and Ingegerd Johansson and Khaw, {Kay Tee} and Lohman, {Kurt K.} and Ani Manichaikul and McKeown, {Nicola M.} and Dariush Mozaffarian and Andrew Singleton and Kathleen Stirrups and Jorma Viikari and Zheng Ye and Stefania Bandinelli and In{\^e}s Barroso and Panos Deloukas and Forouhi, {Nita G.} and Albert Hofman and Yongmei Liu and Lyytik{\"a}inen, {Leo Pekka} and North, {Kari E.} and Maria Dimitriou and Goran Hallmans and Mika K{\"a}h{\"o}nen and Claudia Langenberg and Ordovas, {Jose M.} and Uitterlinden, {Andr{\'e} G.} and Hu, {Frank B.} and Kalafati, {Ioanna Panagiota} and Olli Raitakari and Franco, {Oscar H.} and Andrew Johnson and Valur Emilsson and Schrack, {Jennifer A.} and Semba, {Richard D.} and Siscovick, {David S.} and Arnett, {Donna K.} and Borecki, {Ingrid B.} and Franks, {Paul W.} and Kritchevsky, {Stephen B.} and Loos, {Terho Lehtim{\"a}ki Ruth J.F.} and Marju Orho-Melander and Rotter, {Jerome I.} and Wareham, {Nicholas J.} and Witteman, {Jacqueline C.M.} and Luigi Ferrucci and George Dedoussis and Cupples, {L. Adrienne} and Nettleton, {Jennifer A.}",

year = "2013",

month = jun,

day = "1",

doi = "10.3945/ajcn.112.052183",

language = "English",

volume = "97",

pages = "1395--1402",

journal = "American Journal of Clinical Nutrition",

issn = "0002-9165",

number = "6",

}

Tanaka, T, Ngwa, JS, Van Rooij, FJA, Zillikens, MC, Wojczynski, MK, Frazier-Wood, AC, Houston, DK, Kanoni, S, Lemaitre, RN, Luan, JNA, Mikkilä, V, Renstrom, F, Sonestedt, E, Zhao, JH, Chu, AY, Qi, L, Chasman, DI, De Oliveira Otto, MC, Dhurandhar, EJ, Feitosa, MF, Johansson, I, Khaw, KT, Lohman, KK, Manichaikul, A, McKeown, NM, Mozaffarian, D, Singleton, A, Stirrups, K, Viikari, J, Ye, Z, Bandinelli, S, Barroso, I, Deloukas, P, Forouhi, NG, Hofman, A, Liu, Y, Lyytikäinen, LP, North, KE, Dimitriou, M, Hallmans, G, Kähönen, M, Langenberg, C, Ordovas, JM, Uitterlinden, AG, Hu, FB, Kalafati, IP, Raitakari, O, Franco, OH, Johnson, A, Emilsson, V, Schrack, JA, Semba, RD, Siscovick, DS, Arnett, DK, Borecki, IB, Franks, PW, Kritchevsky, SB, Loos, TLRJF, Orho-Melander, M, Rotter, JI, Wareham, NJ, Witteman, JCM, Ferrucci, L, Dedoussis, G, Cupples, LA & Nettleton, JA 2013, 'Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake', American Journal of Clinical Nutrition, vol. 97, no. 6, pp. 1395-1402. https://doi.org/10.3945/ajcn.112.052183

TY - JOUR

T1 - Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake

AU - Tanaka, Toshiko

AU - Ngwa, Julius S.

AU - Van Rooij, Frank J.A.

AU - Zillikens, M. Carola

AU - Wojczynski, Mary K.

AU - Frazier-Wood, Alexis C.

AU - Houston, Denise K.

AU - Kanoni, Stavroula

AU - Lemaitre, Rozenn N.

AU - Luan, Jia N.An

AU - Mikkilä, Vera

AU - Renstrom, Frida

AU - Sonestedt, Emily

AU - Zhao, Jing Hua

AU - Chu, Audrey Y.

AU - Qi, Lu

AU - Chasman, Daniel I.

AU - De Oliveira Otto, Marcia C.

AU - Dhurandhar, Emily J.

AU - Feitosa, Mary F.

AU - Johansson, Ingegerd

AU - Khaw, Kay Tee

AU - Lohman, Kurt K.

AU - Manichaikul, Ani

AU - McKeown, Nicola M.

AU - Mozaffarian, Dariush

AU - Singleton, Andrew

AU - Stirrups, Kathleen

AU - Viikari, Jorma

AU - Ye, Zheng

AU - Bandinelli, Stefania

AU - Barroso, Inês

AU - Deloukas, Panos

AU - Forouhi, Nita G.

AU - Hofman, Albert

AU - Liu, Yongmei

AU - Lyytikäinen, Leo Pekka

AU - North, Kari E.

AU - Dimitriou, Maria

AU - Hallmans, Goran

AU - Kähönen, Mika

AU - Langenberg, Claudia

AU - Ordovas, Jose M.

AU - Uitterlinden, André G.

AU - Hu, Frank B.

AU - Kalafati, Ioanna Panagiota

AU - Raitakari, Olli

AU - Franco, Oscar H.

AU - Johnson, Andrew

AU - Emilsson, Valur

AU - Schrack, Jennifer A.

AU - Semba, Richard D.

AU - Siscovick, David S.

AU - Arnett, Donna K.

AU - Borecki, Ingrid B.

AU - Franks, Paul W.

AU - Kritchevsky, Stephen B.

AU - Loos, Terho Lehtimäki Ruth J.F.

AU - Orho-Melander, Marju

AU - Rotter, Jerome I.

AU - Wareham, Nicholas J.

AU - Witteman, Jacqueline C.M.

AU - Ferrucci, Luigi

AU - Dedoussis, George

AU - Cupples, L. Adrienne

AU - Nettleton, Jennifer A.

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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. Design: 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). Conclusion: 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).

AB - 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. Design: 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). Conclusion: 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).

UR - http://www.scopus.com/inward/record.url?scp=84875922294&partnerID=8YFLogxK

U2 - 10.3945/ajcn.112.052183

DO - 10.3945/ajcn.112.052183

M3 - Article

C2 - 23636237

AN - SCOPUS:84875922294

SN - 0002-9165

VL - 97

SP - 1395

EP - 1402

JO - American Journal of Clinical Nutrition

JF - American Journal of Clinical Nutrition

IS - 6

ER -

Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake

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