epistasis and sib pair linkage

David Curtis dcurtis at hgmp.mrc.ac.uk
Tue Jun 20 04:54:28 EST 1995

mbmiller at SIRRONALD.WUSTL.EDU (Mike Miller) wrote:

>We would like for our nonparametric methods of linkage analysis (e.g.,
>affected sib pair methods) to be able to detect disease susceptibility
>loci under any model of inheritance--we would like them to be
>"model-free."  I find it interesting that there can be models where all of
>the genetic variance is accounted for by two loci, but there is no
>additive genetic variance, no dominance genetic variance, and thus no
>genic effect at either locus to be detected by the sib pair method.  The 
>IBD distribution at loci A and B would equal the null distribution (1/4, 
>1/2, 1/4, for 0, 1, 2).

>Suppose we have a disease with population prevalence K, and there are two 
>alleles _of_equal_frequency_ at each of two loci, and the following table 
>shows the penetrance of each two-locus genotype:

>      BB   Bb   bb
>     ===  ===  ===
>AA   2K    0   2K
>Aa    K    K    K
>aa    0   2K    0

This is such a contrived example that I don't find it particularly
worrying. Being heterozygous at B prevents the disease in the presence
of AA, while being homozygous for either allele prevents disease in
the presence of aa? It's hard to think of  any biological mechanism
which could plausibly produce these penetrances. Also, for a fairly
rare disease we'd be talking about a tiny (neglible) effect on risk -
for example with schizophrenia we'd be talking about a risk of 0.02
compared with the population prevalence of 0.01.

There are plenty of problems with sib pair methods, but I don't see
this as being a major one, and I wouldn't lose too much sleep over it
if I were you.

Dave Curtis (dcurtis at hgmp.mrc.ac.uk)
Institute of Psychiatry, London 

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