title: Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites.
abstract: Genetic factors modifying the blood metabolome have been investigated through genome-wide association studies (GWAS) of common genetic variants and through exome sequencing. We conducted a whole-genome sequencing study of common, low-frequency and rare variants to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults. We focused the analysis on 644 metabolites with consistent levels across three longitudinal data collections. Genetic sequence variations at 101 loci were associated with the levels of 246 (38%) metabolites (P ≤ 1.9 × 10-11). We identified 113 (10.7%) among 1,054 unrelated individuals in the cohort who carried heterozygous rare variants likely influencing the function of 17 genes. Thirteen of the 17 genes are associated with inborn errors of metabolism or other pediatric genetic conditions. This study extends the map of loci influencing the metabolome and highlights the importance of heterozygous rare variants in determining abnormal blood metabolic phenotypes in adults.
authors.affiliation: Human Longevity, Inc., San Diego, California, USA.
authors.forename: Tao
authors.identifier: http://orcid.org/0000-0002-7052-9546
authors.initials: T
authors.lastname: Long
authors.affiliation: Human Longevity, Inc., San Diego, California, USA.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0003-1045-2660
authors.initials: M
authors.lastname: Hicks
authors.affiliation: Human Longevity, Inc., San Diego, California, USA.
authors.forename: Hung-Chun
authors.identifier: http://orcid.org/0000-0002-4980-8508
authors.initials: HC
authors.lastname: Yu
authors.affiliation: Human Longevity, Inc., San Diego, California, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Biggs
authors.affiliation: Human Longevity, Inc., San Diego, California, USA.
authors.forename: Ewen F
authors.initials: EF
authors.lastname: Kirkness
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College, London, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Menni
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College, London, UK.
authors.forename: Jonas
authors.identifier: http://orcid.org/0000-0002-9693-1859
authors.initials: J
authors.lastname: Zierer
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College, London, UK.
authors.forename: Kerrin S
authors.identifier: http://orcid.org/0000-0003-4566-0005
authors.initials: KS
authors.lastname: Small
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College, London, UK.
authors.forename: Massimo
authors.identifier: http://orcid.org/0000-0002-2167-7470
authors.initials: M
authors.lastname: Mangino
authors.affiliation: Human Longevity, Inc., San Diego, California, USA.|Health Nucleus, San Diego, California, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Messier
authors.affiliation: Human Longevity Singapore, Pte. Ltd., Singapore.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Brewerton
authors.affiliation: Human Longevity Singapore, Pte. Ltd., Singapore.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Turpaz
authors.affiliation: Human Longevity, Inc., San Diego, California, USA.|Health Nucleus, San Diego, California, USA.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Perkins
authors.affiliation: Metabolon, Inc., Durham, North Carolina, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Evans
authors.affiliation: Metabolon, Inc., Durham, North Carolina, USA.
authors.forename: Luke A D
authors.initials: LA
authors.lastname: Miller
authors.affiliation: Metabolon, Inc., Durham, North Carolina, USA.
authors.forename: Lining
authors.initials: L
authors.lastname: Guo
authors.affiliation: Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: C Thomas
authors.initials: CT
authors.lastname: Caskey
authors.affiliation: J. Craig Venter Institute, La Jolla, California, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.affiliation: Human Longevity, Inc., San Diego, California, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Garner
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College, London, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Human Longevity, Inc., San Diego, California, USA.|J. Craig Venter Institute, La Jolla, California, USA.
authors.forename: J Craig
authors.initials: JC
authors.lastname: Venter
authors.affiliation: Human Longevity, Inc., San Diego, California, USA.|J. Craig Venter Institute, La Jolla, California, USA.
authors.forename: Amalio
authors.identifier: http://orcid.org/0000-0001-6290-7677
authors.initials: A
authors.lastname: Telenti
mesh_terms: D000328:Adult; D000368:Aged; D001769:Blood; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D055442:Metabolome / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D040641:Quantitative Trait Loci