Allele sharing method for fine mapping linkage loci: application to bipolar affective disorder
Abstract
Large family studies of complex disorders can be used to detect a genomic region
linked with a particular illness. Where multiple families are found with common
regions of linkage, this could be due to an ancestral mutation common to these
families. In this thesis, I describe a method for studying allele sharing in families that
share a linkage region, to identify a common founder mutation, thus maximising the
results of replicated linkage studies.
The method tests the hypothesis that the evidence for shared linkage is derived from
the sharing of a common affected ancestor. By comparing the allelic similarity of
haplotypes across common linkage regions, it is possible to identify any regions that
are identical by descent between the families. A method of permutation analysis
followed by a nested permutation technique have been developed to assess the
statistical significance of allele sharing scores. Chapter 3 describes the proof of
principle of the method through its application to known cystic fibrosis mutations and
through simulated datasets. This provides both a real dataset and a much more
diverse range of simulated conditions on which to test the method. The range of
simulated data was also used to develop a set of criteria for the effective us of the
method.
In Chapter 4, the allele sharing method was applied to two replicated linkage regions
on chromosome 4p15-16 that segregate with bipolar affective disorder. This was
done over two phases, first taking in markers covering the genic regions of the shared
linkage region and then followed up with a complete coverage of the region. This
analysis identified a 200kb region with significant confidence within the 8Mb of the
two linkage regions. The study of this region presents a clear example of how
replicated linkage results that are caused by some founder effect, can be examined,
and refined using this allele sharing method to vastly reduce the region under
investigation.