Fig. 2

Genetic proxies for environmental insults, with examples given for poliovirus infection and mercury exposure. This illustrates the Mendelian randomisation approach to infer a causal role of environmental factors in ALS. ALS is associated with the environmental factors via an intermediate status, and the environmental interacting genes (dashed line). But the effect of the interacting genes is directional and facilitates the establishment of the intermediate status. Such an effect can only occur in the presence of environmental insults. The susceptibility alleles of the interacting genes will not be reversely affected by the ALS outcome since all genotypes are determined at conception