Schlagwort-Archive: ormdl3

Update on asthma and allergy genes

Even the most recent attempt by Open Targets integrating basically everything

GWAS Catalog and UK Biobank) with transcriptomic, proteomic and epigenomic data, including systematic disease–disease and disease–molecular trait colocalization results across 92 cell types and tissues … trained a machine-learning model … to distinguish causal genes from neighboring genes, outperforming a naive distance-based model

ended up with nothing new

I am glad to see, however, that my criticism of the ORMDL3 hype has been taken up by other authors as well

In the first report of the association of the 17q21 locus with asthma, Moffatt et al. suggested ORMDL3 as a promising candidate on the basis of gene expression studies in EBV-transformed lymphoblastoid cell lines 5. However, the function of ORMDL3 remains to be fully elucidated and it is possible that other genes in this region, or more distant genes, contain the true causal variants.

while ORMDL3 isn’t appearing at all in the above analysis. So ORMDL3 seems to suffer the same fate as FcER1b/MS4A2 identified by the same group.

ORMDL3 graduated

Given my sceptical view that ORMDL3 is really an asthma gene (that may be even shared by the authors of the initial association) the train has now departed with more groups speculating about ORMDL3 function.
For example this new paper by Gerard Cantero-Recasens is about the unfolded protein response (UPR) that may be triggered by a putative loss of function mutation in ORMDL3 via a Ca2+ decrease in the ER. Although I am quite intrigued about the fact that the story now moves to calcium and vitamin D, we are far away from any conclusive evidence.

Addenddum 3.3.2010

And here is another paper that associates ORMDL3 to the sphingolipid metabolism. Although that may be also an interesting pathway (given a bulk of literature not cited in the paper ( more, more, more, more) I still wonder if this is wishful thinking. The authors do not touch the main problem – the weak connection of some genomic variants in that region to ORMDL3 function to asthma pathogenesis.

A fancy new category for a GWA result: same direction

screenshot7 Isn’t that a funny new category as reported in the last asthma genome scan – “same direction”? Should that provide evidence that isn’t there?
Of 10 samples only one replicates (FHS) and one shows borderline (COP) association to PDE4D / rs 1588265.

… in the absence of biological evidence we cannot exclude the possibility that the associations we measured were due to chance only

yea, yea.
BTW Also here – magically, previously associated genes disappear