This p-QtL analysis can be performed on a large scale using cells representing a population and specific ethnicity. Such work has been reported early in 2013 by Wu et al in their publication titled "Variation and Genetic Control of Protein Abundance in Humans" in Nature journal. one can access full text here : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789121/ .
They have used lymphoblastoid cell lines which were sequenced under HapMap and 1000 genomes project.
One question often asked by the young researchers is that how and when to decide which mechanisms to investigate that facilitates our understanding on the function of any protein modulated by the genetic variant?
So a static genetic marker could be identified that can explain a phenotype, which can be helpful for e.g. in stratification of patients
A clear and definitive questioning stratergy is what PM Team thinks should be developed by the young researchers instead of using all the advanced technology and resources we have. One must clearly look for supporting and the contradicting literature before initiating a study after asking a precise, clear research question. Which is the best was than collecting the data possible using technology and resources and then deciding what we can get out of all this data.
What if there is a genetic variant correlation with mRNA sequence – Then functional problem might exists or at least this variant is in LD with some other variant which is changing the protein sequence and thus function. Possibility of changes in amount of the protein exists (if this variant responsible for change in amino acid sequence is linked to another variant that is changing the transcription process) via transcription mechanisms.
What if a genetic variant is correlated with the amount of mRNA—Functional relevance in relation to the amount of protein available, but one must remember that even more amount is produced, if the person has a defective variant in the exonic region (homozygous status), then it is meaningless.
What is there is no correlation of mRNA and the protein levels probably other epigenetic mechanisms such as miRNA at the level of translation plays a role.
What if there is no correlation between amount of the protein and its function, possibly post-translational mechanisms plays a major role. Thus, one must think of the steps and approaches, before the study plan instead of using fancy technologies available (to make a meaningful outcome that can have a real translation in clinic).
1) First, observe the function change (Functional studies, In silico simulations) due to a genetic variation resulting an amino acid change, or frame shift or splicing defect or stop codon then investigate them in a large clinical studies of homogeneous population (if possible). Vice versa possible to first find an association by candidate gene selection based either on the physiology or expert opinion or by open approach and then investigate the functionality of the identified variants in functional studies.
2) If the associated variant with phenotype is in promoter region or intronic or intergenic region, look for correlation of this variant with mRNA expression and then the protein levels. Till now the focus is mainly on the genetic mechanisms especially on the variants
3) What if there is no correlation of the promoter region variant and the mRNA levels? Then focus on the epigenetic mechanisms such as methylation to explain why there is no direct relation of variants with mRNA expression.
4) What if you have the correlation of variants with mRNA expression but not with protein expression, then focus on the miRNA mediated mechanisms.
5) What if there is correlation of the variants with protein levels but the levels of proteins not related to the function observed. Then focus on the post-translational mechanisms.
Thus, one must identify the level of regulation that is distributed at various levels of either transcription, or translation or post-translational level. Please note that complex scenarios might exists than this simple explanation.