Genetic variants that sit within (and sometimes near) a target gene are referred to as "cis-variants". Genetic variants that sit outside (and usually far away from) a target gene are referred to as "trans-variants".
In an MR context, cis-variants are particularly useful to use as instrumental variables (IVs), as the function of these genetic variants are usually known. For example, there are several single nucleotide polymorphisms (SNPs) within the CRP gene that are commonly used as IVs in MR analyses, as the genetic variation changes the protein sequence and thus directly impacts the levels of the C-reactive protein (CRP) without the likelihood of bias from horizontal pleiotropy. MR analyses where gene expression is the exposure of interest also benefits more from using cis-variants. However, given that most traits are complex and polygenic (i.e., impacted by many genetic variants, each usually with a small effect), such cis-variants are infrequently used in the MR literature. Trans-variants are those genetic variants that can be located anywhere on the genome and are peripheral to a particular target gene. In an MR context, trans-variants are most commonly used as IVs because most traits are polygenic, with many genetic contributions from across the genome. However, such genetic variants come with the caveat of being possibly highly pleiotropic and, thus, methods that test and account for horizontal pleiotropy are particularly informative.
References
- Swerdlow DI, Kuchenbaecker KB, Shah S, et al. Selecting instruments for Mendelian randomization in the wake of genome-wide association studies. Int J Epidemiol. 2016; 45: 1600-1616
- Lawlor DA, Harbord RM, Timpson NJ, et al. The association of C-reactive protein and CRP genotype with coronary heart disease: findings from five studies with 4,610 cases amongst 18,637 participants. PLoSONE 2008; 3: e3011.
Other terms in 'Useful genetic terms ':
- Allele
- Chromosome
- Copy number variation
- Deoxyribonucleic acid (DNA)
- Gene
- Genetic variant
- Genotype
- Haplotype
- Heterozygous or Heterozygote
- Homozygous or Homozygote
- Linkage disequilibrium (LD)
- Locus
- Palindromic single nucleotide polymorphism (SNP)
- Polygenic risk score (PRS)
- Polymorphism
- Rare variants
- Single nucleotide polymorphism (SNP)