Table 4. Limitations of MR ²⁰.

Limitation	Description	Relevance to Nutritional Psychiatry	Potential Solution
Lack of Available Instruments	Genetic instruments are unavailable for certain exposures	Lack of GWAS for certain nutritional exposures· Also due to poor measurement of particular nutritional exposures (e·g· serum versus intracellular magnesium).	Choose a proxy exposure for which data is available. Continue to review instruments as nutritional GWAS are published.
Weak instrument Bias	Genetic variants that are weakly associated with an exposure (e.g. F-statistic <10) will bias estimates towards the observational estimate in one-sample MR, and to the null in Two-sample MR	Weak instruments for nutritional exposures often result from limited sample sizes of pre-existing GWAS, as well as having a small proportion of variance explained by genetic variation.	Increase sample sizes (e·g· through publicly available GWAS datasets and consortia). Explain more variation in the exposure using allele scores.
Low Power	May be caused by small sample size, low variance explained in the exposure by the SNP, confounding and type 1 error rate.	Inadequate power may result in null results and hinder important further research.	Increase sample size or instrument strength where possible Power for one-sample MR can be calculated using free web application at http://cnsgenomics.com/shiny/mRnd/69
Horizontal Pleiotropy	The association between the genetic variant and the outcome of interest goes through an alternative pathway to the exposure.	Violates a core assumption of MR (figure 1c).	Understand underlying biological function of genetic variants. Use variants directly coding for exposure of interest where possible. Use MR-Egger estimation.
Linkage Disequilibrium	Non-random allocation of alleles in close proximity during meiosis.	Confounding can be introduced by using an allele close to another allele, which affects the outcome of interest through another pathway.	Omit alleles in close genetic proximity to others. Utilise genetic alleles on separate chromosomes Use homogeneous populations where LD structures will be similar
Developmental Compensation (Canalization)	Individual adaptation to a genetic change, which reduces the phenotypic effect of the genetic change·	MR may produce causal estimates that are below the effect achieved by modifying the exposure.	The extent of the impact of canalization on MR is currently unclear.
Population Stratification	Spurious results may result from using mixed populations in which the genetic variant and outcome are associated with a particular genetic background.	Possible limitation of vitamin D in schizophrenia.	Use genetic associations derived from within homogenous populations only· Use summary results statistics that have adequately controlled for population substructure through e.g. principal components analysis or linear mixed models.
Biological Complexity	MR may give misleading results due to overly simplistic interpretation of complex biological pathways.	Several studies have suggested a non-linear association between vitamin D and various outcomes, but standard MR techniques are not able to detect this. Likewise, MR is unable to account for timelimited exposures or sensitive periods, such as intrauterine exposures and psychiatric outcomes.	Improved understanding of biological pathways. Use of novel methods to account for non-linear associations.