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 APOEis an element of2/is an element of3/is an element of4 polymorphism in two Dutch twin cohorts of different age ranges. Across chromosome 19, short tandem repeats and the APOEis an element of2/is an element of3/is an element of4 polymorphism were genotyped in adolescent (aged 13-22 years) and adult (aged 3462 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 APOEis an element of2/is an element of3/is an element of4 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 APOEis an element of2/is an element of3/is an element of4 polymorphism with apoE plasma levels completely explained the linkage in the adolescent twins and partly in the adult twins. (C) 2004 Wiley-Liss, Inc.