| dc.description.abstract | Coeliac
disease
is
a
common
(1%
prevalence)
inflammatory
disease
of
the
small
intestine,
involving
the
role
of
tissue
transglutaminase
and
HLA-‐DQ
binding
immuno-‐dominant
wheat
peptides.
The
disease
is
highly
heritable,
however,
at
most
only
40%
of
this
heritability
is
explained
by
HLA-‐DQ
and
risk
variants
from
genome
wide
association
and
fine
mapping
studies.
The
hypothesis
of
the
research
in
this
thesis
is
that
rare
(minor
allele
frequency
<0.5%)
mutations
of
large
effect
size
(odds
ratios
~2
–
5)
exist,
especially
in
multiply
affected
pedigrees,
which
account
for
the
missing
heritability
of
disease.
NimbleGen
exome
capture
and
Illumina
GAIIx
high
throughput
sequencing
was
performed
in
75
coeliac
disease
individuals
from
55
multiply
affected
families.
Candidate
genes
were
chosen
from
various
analytical
strategies:
linkage,
shared
variants
between
multiple
related
subjects
and
gene
burden
tests
for
multiple
potentially
causal
variants.
Highly
multiplexed
amplicon
sequencing,
using
Fluidigm
technology,
of
all
RefSeq
exons
from
24
candidate
genes
in
2,304
coeliac
cases
and
2,304
controls
was
performed
to
locate
further
rare
variation.
Gene
burden
tests
on
a
highly
stringent
post
quality
control
dataset
identified
no
significant
associations
(P<1x10-‐3)
at
the
resequenced
candidate
genes.
The
strategy
of
sequencing
multiply
affected
families,
and
deep
follow
up
of
candidate
genes,
has
not
identified
new
disease
risk
mutations.
Common
variants
(and
other
factors,
e.g.
environmental)
may
instead
account
for
familial
clustering
in
this
common
autoimmune
disease | en_US |
