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Combined Association and Linkage Analysis Applied to the APOE Locus

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Author: Beekman, M. · Posthuma, D. · Heijmans, B.T. · Lakenberg, N. · Suchiman, H.E.D. · Snieder, H. · Knijff, P. de · Frants, R.R. · Ommen, G.J.B. van · Kluft, C. · Vogler, G.P. · Slagboom, P.E. · Boomsma, D.I.
Source:Genetic Epidemiology, 4, 26, 328-337
Identifier: 237728
doi: doi:10.1002/gepi.10318
Keywords: ApoE level · Fine-mapping · Quantitative trait locus · Twin pairs · chromosome 19 · cohort analysis · gene locus · gene mapping · genetic association · genetic linkage · genetic polymorphism · genotype · linkage analysis · lipoprotein blood level · quantitative trait locus · short tandem repeat · twins · Adolescent · Adult · Apolipoprotein E2 · Apolipoprotein E3 · Apolipoprotein E4 · Apolipoproteins E · Chromosomes, Human, Pair 19 · Cohort Studies · Female · Genotype · Humans · Linkage (Genetics) · Lod Score · Male · Netherlands · Polymorphism, Genetic · Quantitative Trait, Heritable · Genetta


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 APOEε2/ε3/ε4 polymorphism in two Dutch twin cohorts of different age ranges. Across chromosome 19, short tandem repeats and the APOEε2/ε3/ε4 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 APOEε2/ε3/ε4 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 APOEε2/ε3/ε4 polymorphism with apoE plasma levels completely explained the linkage in the adolescent twins and partly in the adult twins. © 2004 Wiley-Liss, Inc. Chemicals / CAS: Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E