title: Combined association and linkage analysis applied to the APOE locus.
abstract: Combined association and linkage analysis is a powerful tool for pinpointing functional quantitative traits (QTLs) responsible for regions of significant linkage identified in genome-wide scans. We applied this technique to apoE plasma levels and the APOEepsilon2/epsilon3/epsilon4 polymorphism in two Dutch twin cohorts of different age ranges. Across chromosome 19, short tandem repeats and the APOEepsilon2/epsilon3/epsilon4 polymorphism were genotyped in adolescent (aged 13-22 years) and adult (aged 34-62 years) Dutch twins. In both samples, evidence for indicative linkage with plasma apoE levels was found (maximum LOD score (MLS)=0.8, MLS=2.5, respectively) at 19q13.32. These linkage regions included the APOE locus. As expected, the APOEepsilon2/epsilon3/epsilon4 polymorphism was strongly associated with apoE plasma levels in both samples. An extension of the between/within families association test developed by Fulker et al. ([1999] Am. J. Hum. Genet. 64:259-267) showed that these associations were not due to population stratification. The combined association and linkage analyses revealed that the association of the APOEepsilon2/epsilon3/epsilon4 polymorphism with apoE plasma levels completely explained the linkage in the adolescent twins and partly in the adult twins.
authors.affiliation: Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Posthuma
authors.forename: Bastiaan T
authors.initials: BT
authors.lastname: Heijmans
authors.forename: Nico
authors.initials: N
authors.lastname: Lakenberg
authors.forename: H Eka D
authors.initials: HE
authors.lastname: Suchiman
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
authors.forename: Peter
authors.initials: P
authors.lastname: de Knijff
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Gert Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: Cornelis
authors.initials: C
authors.lastname: Kluft
authors.forename: George P
authors.initials: GP
authors.lastname: Vogler
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
mesh_terms: D000293:Adolescent; D000328:Adult; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19; D015331:Cohort Studies; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D009426:Netherlands; D011110:Polymorphism, Genetic; D019655:Quantitative Trait, Heritable
chemical_list: D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E