Complex diseases mapped by linkage?

David Curtis dcurtis at
Tue May 30 04:42:04 EST 1995

In article <11386 at> mjg5 at (ShereKhan) writes:

>In article <dcurtis.169.000E1A8A at> dcurtis at (David Curtis) writes:

>>example, senile onset Alzheimer's disease is probably pushing it a bit. 

>HIya, I was recently doing research into the fos protooncogene and came across
>various abstracts for and againts this gene being a candidate for this disease.
>Anyway, as I understand it I think the AD gene has been localised at least to
>chromosome 14, q24.3

The chromosome 14 locus is for the Mendelian, pre-senile form. The only gene 
implicated in the senile form is apolipoprotein E, but I said that was pushing 
it a bit because my understanding of the history of its discovery is that 
linkage played very little role. There were some weak positive linkage results 
in that region but most of the evidence implicating the region came from 
association studies. Similarly, I think most regions implicated in diabetes 
and cardiovascular disease have been through association. There may be some 
complex diseases which have produced really definite evidence for linkage, but 
it would be nice to have examples where the actual gene has been identified.

By "complex" I meant "not exhibiting Mendelian patterns of inheritance". So 
either incomplete penetrance, or phenocopies, or both. Locus heterogeneity (as 
in early-onset Alzheimer's) doesn't really count in this case because you only 
find out about it after you've got linkage. I think breast cancer is OK, 
because even if the BRCA1 and BRCA2 mutations are completely Mendelian (are 
they?) it's a common disease which isn't generally Mendelian and so in the 
analysis one has to cope with the situation that one is never really sure 
which individuals and which families represent true genetic cases. We're 
interested in things like e.g. autism, manic depression and schizophrenia. 
Some of our families _might_ be more-or-less Mendelian but over all the 
diseases certainly aren't. So I was looking for nice examples to give those 
pessimists who doubt we will ever find anything using a linkage strategy.

Dave Curtis (dcurtis at

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