title: Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.
abstract: Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (β = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (β = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits.
authors.affiliation: Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Hochner
authors.affiliation: Département de Mathématiques, Université de Sherbrooke and Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Allard
authors.affiliation: Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Einat
authors.initials: E
authors.lastname: Granot-Hershkovitz
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America; Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Sitlani
authors.affiliation: Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sazdovska
authors.affiliation: Department of Statistics, University of Auckland, Auckland, New Zealand.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Barbara
authors.initials: B
authors.lastname: McKnight
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rice
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Enquobahrie
authors.affiliation: Harvard Medical School and General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.affiliation: Institute of Human Genetics, University of California, San Francisco, California, United States of America; Cardiovascular Research Institute, University of California, San Francisco, California, United States of America; Department of Dermatology, University of California, San Francisco, California, United States of America.
authors.forename: Pui
authors.initials: P
authors.lastname: Kwok
authors.affiliation: Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, Massachusetts, United States of America.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hivert
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Felicia
authors.initials: F
authors.lastname: Gomez
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands.
authors.forename: Cornelia
authors.initials: C
authors.lastname: van Duijn
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Stamatoyannopoulos
authors.affiliation: Department of Genetics and Metabolism, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Vardiella
authors.initials: V
authors.lastname: Meiner
authors.affiliation: Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Manor
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Friedlander
authors.affiliation: New York Academy of Medicine, New York, New York, United States of America.
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
mesh_terms: D050154:Adiposity / Q000235:genetics*; D000328:Adult; D053299:Apolipoprotein B-100 / Q000235:genetics*; D015992:Body Mass Index; D002784:Cholesterol / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics; D008297:Male; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D055105:Waist Circumference / Q000235:genetics; D049629:Waist-Hip Ratio; D055815:Young Adult
chemical_list: C569471:APOB protein, human; D053299:Apolipoprotein B-100; D007328:Insulin; D002784:Cholesterol; D005947:Glucose