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Title: Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Author
item MERINO, JORDI - Massachusetts General Hospital
item DASHTI, HASSAN - Massachusetts General Hospital
item LI, SHERLY - University Of Cambridge
item SARNOWSKI, CHLOE - Boston University School Of Public Health
item JUSTICE, ANNE - University Of North Carolina
item GRAFF, MISA - University Of North Carolina
item PAPOUTSAKIS, CONSTANTINA - Academy Of Nutrition And Dietetics
item SMITH, CAREN - Tufts University
item DEDOUSSIS, GEORGE - Harokopio University Of Athens
item LEMAITRE, ROZENN - University Of Washington
item WOJCZYNSKI, MARY - Washington University School Of Medicine
item MANNISTO, SATU - University Of Helsinki
item NGWA, JULIUS - Boston University School Of Public Health
item KHO, MINJUNG - University Of Michigan
item AHLUWALIA, TARUNVEER - University Of Copenhagen
item PERVJAKOVA, NATALIA - University Of Helsinki
item HOUSTON, DENISE - Wake Forest School Of Medicine
item BOUCHARD, CLAUDE - Pennington Biomedical Research Center
item HUANG, TAO - Nanyang Technological University
item ORHO-MELANDER, MARJU - Lund University
item FRAZIER-WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC)
item MOOK-KANAMORI, DENNIS - Leiden University Medical Center
item PERUSSE, LOUIS - Laval University
item PENNELL, CRAIG - University Of Western Australia
item DE VRIES, PAUL - University Of Texas Health Science Center
item VOORTMAN, TRUDY - Erasmus Medical Center
item LI, OLIVIA - Hospital For Sick Children (SICKKIDS)
item KANONI, STAVROULA - Queen Mary University Of London
item ROSE, LYNDA - Brigham & Women'S Hospital
item LEHTIMAKI, TERHO - University Of Tampere
item ZHAO, JING - University Of Cambridge
item FEITOSA, MARY - Washington University School Of Medicine
item LUAN, JIAN'AN - University Of Cambridge
item MCKEOWN, NICOLA - Tufts University
item SMITH, JENNIFER - University Of Michigan
item HANSEN, TORBEN - University Of Copenhagen
item EKLUND, NIINA - University Of Helsinki
item NALLS, MICHAEL - National Institute On Aging (NIA, NIH)
item RANKINEN, TUOMO - Pennington Biomedical Research Center
item HUANG, JINYAN - Shanghai Institute Of Technology
item HERNANDEZ, DENA - National Institute On Aging (NIA, NIH)
item SCHULZ, CHRISTINA - Lund University
item MANICHAKUL, ANI - University Of Virginia
item LI-GAO, RUIFANG - Leiden University
item VOHL, MARIE - Laval University
item WANG, CAROL - University Of Western Australia
item VAN ROOIJ, FRANK - Erasmus Medical Center
item SHIN, JEAN - Hospital For Sick Children (SICKKIDS)
item KALAFATI, IOANNA - Harokopio University Of Athens
item DAY, FELIX - University Of Cambridge
item RIDKER, PAUL - Brigham & Women'S Hospital
item KAHONEN, MIKA - University Of Tampere
item SISCOVICK, DAVID - New York Academy Of Medicine
item LANGENBERG, CLAUDIA - University Of Cambridge
item ZHAO, WEI - University Of Michigan
item ASTRUP, ARNE - University Of Copenhagen
item KNEKT, PAUL - University Of Helsinki
item GARCIA, MELISSA - National Institute On Aging (NIA, NIH)
item RAO, D - Washington University School Of Medicine
item QI, QIBIN - Albert Einstein College Of Medicine
item FERRUCCI, LUIGI - National Institute On Aging (NIA, NIH)
item ERICSON, ULRIKA - Lund University
item BLANGERO, JOHN - University Of Texas Rio Grande Valley
item HOFMAN, ALBERT - Erasmus Medical Center
item PAUSOVA, ZDENKA - Hospital For Sick Children (SICKKIDS)
item WAREHAM, NICK - University Of Cambridge
item KARDIA, SHARON - University Of Michigan
item PEDERSON, OLUF - University Of Copenhagen
item JULA, ANTTI - University Of Helsinki
item CURRAN, JOANNE - University Of Texas Rio Grande Valley
item ZILLIKENS, M - Erasmus Medical Center
item VIIKARI, JORMA - University Of Turku
item FOROUHI, NITA - University Of Cambridge
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LIESKE, JOHN - Mayo Clinic
item RISSANEN, HARRI - University Of Helsinki
item UITTERLINDEN, ANDRE - Erasmus Medical Center
item RAITAKARI, OLLI - University Of Turku
item KIEFTE-DE JONG, JESSICA - Erasmus Medical Center
item DUPUIS, JOSEE - Boston University School Of Public Health
item ROTTER, JEROME - Harbor-Ucla Medical Center
item NORTH, KARI - University Of North Carolina
item SCOTT, ROBERT - University Of Cambridge
item PROVINCE, MICHAEL - Washington University School Of Medicine
item PEROLA, MARKUS - University Of Helsinki
item CUPPLES, L - Boston University School Of Public Health
item TURNER, STEPHEN - Mayo Clinic
item SORENSON, THORKILD - University Of Copenhagen
item SALOMAA, VEIKKO - University Of Helsinki
item LIU, YONGMEI - Wake Forest University
item SUNG, YUN - Washington University School Of Medicine
item BANDINELLI, STEFANIA - Azienda Sanitaria Di Firenze
item RICH, STEPHEN - University Of Virginia
item LYYTIKAINEN, LEO - University Of Tampere
item CHASMAN, DANIEL - Brigham & Women'S Hospital
item CHU, AUDREY - Brigham & Women'S Hospital
item TANAKA, TOSHIKO - National Institute On Aging (NIA, NIH)

Submitted to: Molecular Psychiatry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/10/2018
Publication Date: 7/9/2018
Citation: Merino, J., Dashti, H., Li, S., Sarnowski, C., Justice, A., Graff, M., Papoutsakis, C., Smith, C., Dedoussis, G., Lemaitre, R., Wojczynski, M., Mannisto, S., Ngwa, J., Kho, M., Ahluwalia, T., Pervjakova, N., Houston, D., Bouchard, C., Huang, T., Orho-Melander, M., Frazier-Wood, A., Mook-Kanamori, D., Perusse, L., Pennell, C., De Vries, P., Voortman, T., Li, O., Kanoni, S., Rose, L., Lehtimaki, T., Zhao, J.H., Feitosa, M., Luan, J., McKeown, N., Smith, J., Hansen, T., Eklund, N., Nalls, M., Rankinen, T., Huang, J., Hernandez, D., Schulz, C.A., Manichakul, A., Li-Gao, R., Vohl, M.C., Wang, C., Van Rooij, F., Shin, J., Kalafati, I., Day, F., Ridker, P., Kahonen, M., Siscovick, D., Langenberg, C., Zhao, W., Astrup, A., Knekt, P., Garcia, M., Rao, D.C., Qi, Q., Ferrucci, L., Ericson, U., Blangero, J., Hofman, A., Pausova, Z., Wareham, N., Kardia, S., Pederson, O., Jula, A., Curran, J., Zillikens, M.C., Viikari, J., Forouhi, N., Ordovas, J., Lieske, J., Rissanen, H., Uitterlinden, A., Raitakari, O., Kiefte-De Jong, J., Dupuis, J., Rotter, J., North, K., Scott, R., Province, M., Perola, M., Cupples, L., Turner, S., Sorenson, T., Salomaa, V., Liu, Y., Sung, Y.J., Bandinelli, S., Rich, S., Lyytikainen, L.P., Chasman, D., Chu, A., Tanaka, T. 2018. Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0079-4.
DOI: https://doi.org/10.1038/s41380-018-0079-4

Interpretive Summary: The macronutrient content of our diet refers to the relative contributions of fat, carbohydrate, and protein to overall intake. Macronutrient intake is a modifiable risk factor for complex metabolic diseases, but we do not know why people choose different dietary macronutrient intakes. While there are environmental factors that predict macronutrient intake, there may also be innate genetic factors. To discover whether this is the case, we used data from over 20 studies across Europe and North America and scanned the genome for loci where variation associates with macronutrient intake. We found associations with loci in or near four genes: in FGF21 with intake of all three macronutrients, in RARB with carbohydrate intake, and in FTO and DRAM1 with protein intake. The functions of FGF21 and DRAM1 are poorly understood and should be examined in future studies, however FTO is the most well known genetic risk factor for obesity, and RARB is expressed in the central nervous system. Together these highlight the role of macronutrient intake in obesity risk, and the importance of behavioral factors in diseases related to food intake, respectively. If replicated and validated, this study may provide important information for predicting disease risk, and/or understanding the associations of macronutrients with disease risk.

Technical Abstract: Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P<1 X 10^-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.