The Meaning of "Cause" in Genetics

Abstract

Causation has multiple distinct meanings in genetics. One reason for this is meaning slippage between two concepts of the gene: Mendelian and molecular. Another reason is that a variety of genetic methods address different kinds of causal relationships. Some genetic studies address causes of traits in individuals, which can only be assessed when single genes follow predictable inheritance patterns that reliably cause a trait. A second sense concerns the causes of trait differences within a population. Whereas some single genes can be said to cause population-level differences, most often these claims concern the effects of many genes. Polygenic traits can be understood using heritability estimates, which estimate the relative influences of genetic and environmental differences to trait differences within a population. Attempts to understand the molecular mechanisms underlying polygenic traits have been developed, although causal inference based on these results remains controversial. Genetic variation has also recently been leveraged as a randomizing factor to identify environmental causes of trait differences. This technique-Mendelian randomization-offers some solutions to traditional epidemiological challenges, although it is limited to the study of environments with known genetic influences.

Figure 1.

The ABO blood group is often used to show a specific relationship between genotype and phenotype, although two blood types (A and B) are multiply realized by two different genotypes (A, AO and B, BO).

Figure 2.

An unspecific causal relationship between genotype and phenotype. (A) Osteogenesis imperfect (OI) is multiply realized by two different genes: COL1A1 and COL1A2. (B) When effects of these genes are characterized by symptoms, both COL1A1 and COL1A2 are pleiotropic for the same set of traits.

Figure 3.

Norms of reaction that show the phenotypic distribution (y-axis) of difference genotypes (G1, G2, G3) across different environments (E1, E2). (A) A reaction norm where most phenotypic variance is accounted for by genetic variance, (B) where most phenotypic variance is accounted for by genetic variance, (C) where both genetic and environmental variance contribute to phenotypic variance additively, and (D) where genetic and environmental variance interact statistically, a case of G×E. The effects of G on P are relatively stable in A, although not in B, C, or D, as the values of P corresponding to values of G are altered. The effects of G on P are relatively invariant in A, B, and C, although not in D, as there is a functional causal relationship between G and P in these first three, although not the latter.

Figure 4.

The possible causal relationships that may underlie an association between two variables. If X and Y are associated within a population, it may be that X causes Y, Y causes X, or both are caused by another variable, Z.

Figure 5.

The different possible forms of gene–environment correlation. (A) No correlation between genes and environment occurs, and both influence phenotype independently. (B) Genes causally influence environments, corresponding to active and reactive cases of gene–environment correlation. (C) Parental genes causes both the child's genotype and the child's environment (via genetic nurture), correlating the child's genes and environment.