title: An exome array study of the plasma metabolome.
abstract: The study of rare variants may enhance our understanding of the genetic determinants of the metabolome. Here, we analyze the association between 217 plasma metabolites and exome variants on the Illumina HumanExome Beadchip in 2,076 participants in the Framingham Heart Study, with replication in 1,528 participants of the Atherosclerosis Risk in Communities Study. We identify an association between GMPS and xanthosine using single variant analysis and associations between HAL and histidine, PAH and phenylalanine, and UPB1 and ureidopropionate using gene-based tests (P<5 × 10(-8) in meta-analysis), highlighting novel coding variants that may underlie inborn errors of metabolism. Further, we show how an examination of variants across the spectrum of allele frequency highlights independent association signals at select loci and generates a more integrated view of metabolite heritability. These studies build on prior metabolomics genome wide association studies to provide a more complete picture of the genetic architecture of the plasma metabolome.
authors.affiliation: Nephrology Division, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.|Endocrinology Division, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.|Metabolite Profiling, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Rhee
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, Massachusetts 02118, USA.
authors.forename: Qiong
authors.identifier: http://orcid.org/0000-0002-3658-1375
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, 1200 Pressler Street, Houston, Texas 77030, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, Massachusetts 02118, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: National Heart, Lung and Blood Institute's Framingham Heart Study, 73 Mount Wayte Avenue, Framingham, Massachusetts 01702, USA.|Division of Cardiovascular Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Metabolite Profiling, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Deik
authors.affiliation: Metabolite Profiling, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Pierce
authors.affiliation: Metabolite Profiling, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bullock
authors.affiliation: Cardiology Division, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Ho
authors.affiliation: National Heart, Lung and Blood Institute's Framingham Heart Study, 73 Mount Wayte Avenue, Framingham, Massachusetts 01702, USA.|Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: Diabetes Research Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.|Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.affiliation: Cardiology Division, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.|Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
authors.forename: Sek
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, Massachusetts 02118, USA.|National Heart, Lung and Blood Institute's Framingham Heart Study, 73 Mount Wayte Avenue, Framingham, Massachusetts 01702, USA.|Department of Mathematics and Statistics, Boston University, 111 Cummington Mall, Boston, Massachusetts 02215, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.affiliation: National Heart, Lung and Blood Institute's Framingham Heart Study, 73 Mount Wayte Avenue, Framingham, Massachusetts 01702, USA.|Preventive Medicine and Epidemiology, Boston University School of Medicine, 801 Massachusetts Avenue, Boston, Massachusetts 02118, USA.
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.affiliation: Metabolite Profiling, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Clary B
authors.identifier: http://orcid.org/0000-0001-8259-9245
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, Tennessee 37232, USA.|Vanderbilt Heart and Vascular Institute, 1211 Medical Center Drive, Nashville, Tennessee 37232, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, 1200 Pressler Street, Houston, Texas 77030, USA.|Human Genome Sequencing Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: National Heart, Lung and Blood Institute's Framingham Heart Study, 73 Mount Wayte Avenue, Framingham, Massachusetts 01702, USA.|Cardiology Section, Boston Veteran's Administration Healthcare, 1400 VFW Parkway, Boston, Massachusetts 02132, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, 185 Pilgrim Road, Boston, Massachusetts 02215, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
mesh_terms: D059472:Exome / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D055442:Metabolome / Q000235:genetics*; D008875:Middle Aged; D010949:Plasma / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012263:Ribonucleosides / Q000378:metabolism; D014970:Xanthines
chemical_list: D012263:Ribonucleosides; D014970:Xanthines; C005893:xanthosine