Chunk #32 — Reasons to be Concerned about the Published cGxE Literature — The Ingredients of cGxE: The Choice of Genetic and Environmental Variables — The Choice of “G”
variant, the characterization of that variant (or its mode of inheritance) can profoundly impact detection of cGxE. For instance, which allele is assigned as a risk allele, and how many copies of this allele are required to quantify the diathesis, need to be determined. How to model a genotype becomes a particular concern with smaller samples, where homozygotes (individuals who carry two copies of a given allele) of the minor allele are often combined with heterozygotes (individuals who carry one copy of a given allele) in the interest of statistical power, potentially obfuscating the complexity underlying the genetic model. Consider the consequences if one applied this practice to other known genetic outcomes: for example, we know that two copies of one of several of the CFTR mutations are required for the diagnosis of cystic fibrosis (a disorder with a recessive mode of genetic inheritance), and that this is etiologically distinct from the one copy of the HTT trinucelotide expansion required for a diagnosis of Huntington’s disease (a dominant disorder). Imagine the confusion if a prenatal genetic counselor were to ascribe the same degree of vulnerability to a fetus that tests positive for one copy (a carrier, unaffected with disease) versus
