MR Dictionary

Factorial MR

An MR method that explores the separate and joint causal effects of two (or potentially more) exposures on an outcome and is analogous to factorial randomized controlled trial (RCT) designs. Participants in a factorial MR study are categorised into different levels of each exposure based on their genetic instrumental variables (IVs). Where the genetic IV involves multiple single nucleotide polymorphisms (SNPs), categories of high versus low exposure might be defined by being above and below the median of a polygenic risk score (PRS) comprising those SNPs. For a genetic IV that includes a single SNP, the categorisation may be two groups (i.e., one group of homozygotes versus a group of the heterozygotes and other homozygotes together) or three groups (i.e., homozygotes for one allele, heterozygotes, and homozygotes for the other allele). Regression analyses are then conducted with the genetic IV categories.

Genetic IVs for the two (or potentially more) exposures are the categories defined by genetic variants associated with those exposures. These categories need to fulfil the key MR assumptions. Factorial MR may have limited statistical power (in comparison to factorial RCTs and MR of single exposures).

Factorial Mendelian randomization. Adapted with permission from Carter et al. In this example, factorial MR is used to investigate the combined effects of body mass index (BMI) and alcohol on liver disease and liver disease biomarkers. Disease and biomarker levels are compared across the four categories of genetically instrumented combinations of low and high BMI and alcohol levels. Low and high BMI were defined as below or equal to and above the median of a weighted polygenic risk score (PGRS) for BMI, respectively. For low and high alcohol categories, a single candidate genetic variant in the _ADH1B_ gene was used as an instrument and homozygotes for the allele associated with higher alcohol consumption (high) were compared to those who were heterozygotes or homozygotes for the allele associated with lower alcohol consumption.
Figure 2.2 - Factorial Mendelian randomization. Adapted with permission from Carter et al. In this example, factorial MR is used to investigate the combined effects of body mass index (BMI) and alcohol on liver disease and liver disease biomarkers. Disease and biomarker levels are compared across the four categories of genetically instrumented combinations of low and high BMI and alcohol levels. Low and high BMI were defined as below or equal to and above the median of a weighted polygenic risk score (PGRS) for BMI, respectively. For low and high alcohol categories, a single candidate genetic variant in the _ADH1B_ gene was used as an instrument and homozygotes for the allele associated with higher alcohol consumption (high) were compared to those who were heterozygotes or homozygotes for the allele associated with lower alcohol consumption.

References

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