title: Linkage analysis incorporating gene-age interactions identifies seven novel lipid loci: the Family Blood Pressure Program.
abstract: OBJECTIVE
  To detect novel loci with age-dependent effects on fasting (≥ 8 h) levels of total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides using 3600 African Americans, 1283 Asians, 3218 European Americans, and 2026 Mexican Americans from the Family Blood Pressure Program (FBPP).
  
  
  METHODS
  Within each subgroup (defined by network, race, and sex), we employed stepwise linear regression (retention p ≤ 0.05) to adjust lipid levels for age, age-squared, age-cubed, body-mass-index, current smoking status, current drinking status, field center, estrogen therapy (females only), as well as antidiabetic, antihypertensive, and antilipidemic medication use. For each trait, we pooled the standardized male and female residuals within each network and race and fit a generalized variance components model that incorporated gene-age interactions. We conducted FBPP-wide and race-specific meta-analyses by combining the p-values of each linkage marker across subgroups using a modified Fisher's method.
  
  
  RESULTS
  We identified seven novel loci with age-dependent effects; four total cholesterol loci from the meta-analysis of Mexican Americans (on chromosomes 2q24.1, 4q21.21, 8q22.2, and 12p11.23) and three high-density lipoprotein loci from the meta-analysis of all FBPP subgroups (on chromosomes 1p12, 14q11.2, and 21q21.1). These loci lacked significant genome-wide linkage or association evidence in the literature and had logarithm of odds (LOD) score ≥ 3 in the meta-analysis with LOD ≥ 1 in at least two network and race subgroups (exclusively of non-European descent).
  
  
  CONCLUSIONS
  Incorporating gene-age interactions into the analysis of lipids using multi-ethnic cohorts can enhance gene discovery. These interaction loci can guide the selection of families for sequencing studies of lipid-associated variants.
authors.affiliation: Division of Biostatistics, Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Simino
authors.affiliation: Division of Biostatistics, Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Rezart
authors.initials: R
authors.lastname: Kume
authors.affiliation: Division of Statistical Genomics Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Aldi T
authors.initials: AT
authors.lastname: Kraja
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Turner
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Hanis
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Wayne
authors.initials: W
authors.lastname: Sheu
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502.
authors.forename: Ida
authors.initials: I
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Sciences, National Heart, Lung, Blood Institute, Bethesda, Maryland, USA.
authors.forename: Cashell
authors.initials: C
authors.lastname: Jaquish
authors.affiliation: Department of Preventive Medicine and Epidemiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.affiliation: Division of Biostatistics, Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA.|Also Departments of Genetics, Psychiatry, and Mathematics, Washington University in St. Louis, School of Medicine, Missouri, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Rao
mesh_terms: D000328:Adult; D001741:Black or African American; D000367:Age Factors; D001213:Asian; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D001794:Blood Pressure; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003327:Coronary Disease / Q000235:genetics / Q000473:pathology; D005006:Ethnicity; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D017058:Mexican Americans; D008875:Middle Aged; D010641:Phenotype; D040641:Quantitative Trait Loci; D044465:White People / Q000235:genetics
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005819:Genetic Markers; D008055:Lipids; D002784:Cholesterol
keywords: Aging; Cholesterol; Genetics; Gene–age interactions; Linkage; Lipids; Meta-analysis; Triglyceride