Combined association and linkage analysis applied to the APOE locus.
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.
Beekman
Marian
M
Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Posthuma
Daniëlle
D
Heijmans
Bastiaan T
BT
Lakenberg
Nico
N
Suchiman
H Eka D
HE
Snieder
Harold
H
de Knijff
Peter
P
Frants
Rune R
RR
van Ommen
Gert Jan B
GJ
Kluft
Cornelis
C
Vogler
George P
GP
Slagboom
P Eline
PE
Boomsma
Dorret I
DI
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
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E