Research: confounding genetics

Epub: Pirinen et al. Including known covariates can reduce power to detect genetic effects in case-control studies. Nat Genet. 2012 Jul. doi: 10.1038/ng.2346.

“This paper describes another factor to confound the genetics lobby. I suspect that most readers find these studies very confusing. The reason for this is that they are confusing! The genetic revolution has
yet to deliver something that can be taken into the clinic for MS, but
it may someday soon.”

Genome-wide association studies (GWAS) search for associations between genetic variants and disease status, typically via a statistical process called logistic regression. Often there are covariates, such as sex or well-established major genetic factors, that are known to affect disease susceptibility and are independent of tested genotypes at the population level. This anallysis shows theoretically and with data from recent GWAS on MS, psoriasis and ankylosing spondylitis that inclusion of known covariates can substantially reduce power for the identification of associated variants when the disease prevalence is lower than a few percent. Whether the inclusion of such covariates reduces or increases power to detect genetic effects depends on various factors, including the prevalence of the disease studied. When the disease is common (prevalence of >20%), the inclusion of covariates typically increases power, whereas, for rarer diseases, it can often decrease power to detect new genetic associations.

“The other day a patient of mine who has an atypical form of multiple sclerosis, that looks similar to neuromyelitis optica,  arranged to have herself HLA typed. Her reason was to see if she could help differentiate MS from NMO. This is important as the treatments for these two conditions are so different. Was the genetic data helpful? Yes, her HLA type was not the type associated with MS, but a rare variant that is protective of MS. This an other features gave me the confidence to label her as having anti-aquaporin negative NMO and to continue treating her with azathioprine. So yes, in selected cases, genetics may help. I must stress that her case is a very rare and unusual.”

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • So this patient paid for a test which she would not have got on the NHS which helped with her diagnosis? I agree that she had the right to have the test and you had the right to look at the results. Are we going to get to the stage in MS where the govt. says you can have this drug, but if you want that drug (more effective, but more expensive) you will have to pay for it, or pay a top up, as is argued with cancer drugs?

  • Re: "So this patient paid for a test which she would not have got on the NHS which helped with her diagnosis?"

    She obtained the test without my knowledge! I wouldn't never recommend this to MSers who are being investigated in the NHS.

By Prof G



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