Li Bingshan, Leal Suzanne M
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Hum Hered. 2008;65(4):199-208. doi: 10.1159/000112367. Epub 2007 Dec 11.
Missing genotype data can increase false-positive evidence for linkage when either parametric or nonparametric analysis is carried out ignoring intermarker linkage disequilibrium (LD). Previously it was demonstrated by Huang et al. [1] that no bias occurs in this situation for affected sib-pairs with unrelated parents when either both parents are genotyped or genotype data is available for two additional unaffected siblings when parental genotypes are missing. However, this is not the case for autosomal recessive consanguineous pedigrees, where missing genotype data for any pedigree member within a consanguinity loop can increase false-positive evidence of linkage. False-positive evidence for linkage is further increased when cryptic consanguinity is present. The amount of false-positive evidence for linkage, and which family members aid in its reduction, is highly dependent on which family members are genotyped. When parental genotype data is available, the false-positive evidence for linkage is usually not as strong as when parental genotype data is unavailable. For a pedigree with an affected proband whose first-cousin parents have been genotyped, further reduction in the false-positive evidence of linkage can be obtained by including genotype data from additional affected siblings of the proband or genotype data from the proband's sibling-grandparents. For the situation, when parental genotypes are unavailable, false-positive evidence for linkage can be reduced by including genotype data from either unaffected siblings of the proband or the proband's married-in-grandparents in the analysis.
当进行参数分析或非参数分析而忽略标记间连锁不平衡（LD）时，缺失的基因型数据会增加连锁的假阳性证据。此前，Huang等人[1]证明，在这种情况下，对于父母无血缘关系的患病同胞对，如果父母双方都进行了基因分型，或者当父母基因型缺失时，有另外两个未患病同胞的基因型数据，则不会产生偏差。然而，对于常染色体隐性近亲家系并非如此，在近亲环内的任何家系成员缺失基因型数据都会增加连锁的假阳性证据。当存在隐匿性近亲关系时，连锁的假阳性证据会进一步增加。连锁的假阳性证据量以及哪些家庭成员有助于减少这种证据，高度依赖于哪些家庭成员进行了基因分型。当有父母的基因型数据时，连锁的假阳性证据通常不像没有父母基因型数据时那么强。对于一个先证者患病且其表亲父母已进行基因分型的家系，通过纳入先证者其他患病同胞的基因型数据或先证者同胞祖父母的基因型数据，可以进一步减少连锁的假阳性证据。对于父母基因型不可用的情况，在分析中纳入先证者未患病同胞或先证者的已婚祖父母的基因型数据，可以减少连锁的假阳性证据。
