Statistical evaluation is further complicated by the fact that it is not unreasonable to assume that many genes will habor both variants that are protective and predisposing with regard to a given phenotype, as was recently shown for the APP locus in Alzheimer’s disease [20], which with the statistical analysis tools available today will always lead to an underestimation of the genetic contribution of rare variants at a given locus to a phenotype’s heritability [21]. This evidence concerns the gene APP and early-onset autosomal dominant Alzheimer disease.