to their parents. Various groups have shown that the “age signature” of the cell donor appears to be reset by the reprogramming process 55,56, while this reversal does not appear to occur when the somatic cell is directly converted into neurons 57. In particular, hiPSCs derived from older donors do not seem to present significant transcriptional differences with respect to younger donors. Thus, age difference between probands and controls is less of concern when hiPSC-derived samples are compared. Another potential problem of the family design is that it cannot be used to study the influence on the phenotype of genetic risk factors that are shared within each family. To mitigate this, the design should incorporate “diseased” and “non-diseased” families, as commonly done in genomic studies. Indeed, a distinct advantage of a family design is that since it is commonly used in genomics, it may simplify correlations between the genetic variation and aspects of the phenotype that are investigated via hiPSC modeling.
