Causality in Genetics

Abstract

See Research Commentary, p e2 Genetics provide a robust scientific platform for establishing a relationship between a cause, for example, a genetic variant, and an effect, such as a disease phenotype. Yet, causality in genetics is a probabilistic and rarely a deterministic certainty. The causal relationship between a genetic variant and a phenotype is provisional to the conditions and the environment, such as the genetic backgrounds, in which the causal variants and the phenotype operate. The degree of probabilistic causality is, in part, determined by the effect sizes of the genetic variants, which typically follow a gradient ranging from minimal to large.1,2 Genetic variants (single nucleotide variants, small insertion/deletions, and structural variations) with large effect sizes are highly penetrant, as exemplified by variants that are responsible for the single gene disorders with Mendelian patterns of inheritance. In such circumstances, the cause-and-effect relationship is best analyzed through cosegregation and linkage analyses, whereby a logarithm of odds score of ≥3 is considered strong evidence of a genetic linkage but not necessarily a definitive indicator of causality. On the opposite end of the spectrum are the variants that exert modest effect sizes and, hence, are less penetrant. In such cases, establishing a cause-and-effect relationship is more challenging, because such low-penetrant variants typically do not show a clear cosegregation with the phenotype and are often found in the general population as well. Establishing the causal role of the variants is more challenging in small families, and even more so in a single individual. Further compounding the ascertainment of causality is the influence of the genetic backgrounds (modifier genetic variants) and the environmental factors, which are expected to exert greater influence when the effect sizes of the causal genetic variants are rather small. Hence, a genetic variant with a small or moderate …