title: Linkage and association of phospholipid transfer protein activity to LASS4.
abstract: Phospholipid transfer protein activity (PLTPa) is associated with insulin levels and has been implicated in atherosclerotic disease in both mice and humans. Variation at the PLTP structural locus on chromosome 20 explains some, but not all, heritable variation in PLTPa. In order to detect quantitative trait loci (QTLs) elsewhere in the genome that affect PLTPa, we performed both oligogenic and single QTL linkage analysis on four large families (n = 227 with phenotype, n = 330 with genotype, n = 462 total), ascertained for familial combined hyperlipidemia. We detected evidence of linkage between PLTPa and chromosome 19p (lod = 3.2) for a single family and chromosome 2q (lod = 2.8) for all families. Inclusion of additional marker and exome sequence data in the analysis refined the linkage signal on chromosome 19 and implicated coding variation in LASS4, a gene regulated by leptin that is involved in ceramide synthesis. Association between PLTPa and LASS4 variation was replicated in the other three families (P = 0.02), adjusting for pedigree structure. To our knowledge, this is the first example for which exome data was used in families to identify a complex QTL that is not the structural locus.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Rosenthal
authors.forename: James
authors.initials: J
authors.lastname: Ronald
authors.forename: Joseph
authors.initials: J
authors.lastname: Rothstein
authors.forename: Ramakrishnan
authors.initials: R
authors.lastname: Rajagopalan
authors.forename: Jane
authors.initials: J
authors.lastname: Ranchalis
authors.forename: G
authors.initials: G
authors.lastname: Wolfbauer
authors.forename: John J
authors.initials: JJ
authors.lastname: Albers
authors.forename: John D
authors.initials: JD
authors.lastname: Brunzell
authors.forename: Arno G
authors.initials: AG
authors.lastname: Motulsky
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Wijsman
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002874:Chromosome Mapping / Q000379:methods*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D059472:Exome; D008040:Genetic Linkage; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D049294:Phospholipid Transfer Proteins / Q000235:genetics* / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics*; D012307:Risk Factors; D014481:United States / Q000453:epidemiology / Q000208:ethnology; D044465:White People / Q000208:ethnology / Q000235:genetics
chemical_list: D049294:Phospholipid Transfer Proteins; D010088:Oxidoreductases; C108138:dihydroceramide desaturase