Beekman Marian, Posthuma Daniëlle, Heijmans Bastiaan T, Lakenberg Nico, Suchiman H Eka D, Snieder Harold, de Knijff Peter, Frants Rune R, van Ommen Gert Jan B, Kluft Cornelis, Vogler George P, Slagboom P Eline, Boomsma Dorret I
Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Genet Epidemiol. 2004 May;26(4):328-37. doi: 10.1002/gepi.10318.
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.
联合关联与连锁分析是一种强大的工具，可用于精确确定导致全基因组扫描中显著连锁区域的功能定量性状（QTL）。我们将此技术应用于两个不同年龄范围的荷兰双胞胎队列中的载脂蛋白E血浆水平和APOEε2/ε3/ε4多态性。在19号染色体上，对青少年（13 - 22岁）和成年人（34 - 62岁）荷兰双胞胎进行了短串联重复序列和APOEε2/ε3/ε4多态性的基因分型。在两个样本中，均在19q13.32发现了与血浆载脂蛋白E水平指示性连锁的证据（最大对数似然比分数（MLS）分别为0.8和2.5）。这些连锁区域包括APOE基因座。正如预期的那样，APOEε2/ε3/ε4多态性在两个样本中均与载脂蛋白E血浆水平密切相关。Fulker等人（[1999]《美国人类遗传学杂志》64:259 - 267）开发的家族间/家族内关联检验的扩展表明，这些关联并非由于群体分层。联合关联与连锁分析表明，APOEε2/ε3/ε4多态性与载脂蛋白E血浆水平的关联完全解释了青少年双胞胎中的连锁现象，部分解释了成年双胞胎中的连锁现象。
