Research Report 2000 - MDC

Twin studies as a strategy to
identify quantitative trait loci
Andreas Busjahn and Hans-Dieter
Faulhaber have recruited over 200
pairs of monozygotic (MZ) and 120
dizygotic (DZ) normotensive young
twins and the parents of the DZ twins.
The subjects were carefully phenotyped
in terms of blood pressure, blood
pressure in response to provocative
maneuvers, psychological testing, and
serum lipid concentrations. The
strategy is to use a standard twin
analysis to determine heritability
estimates and to distinguish between
hereditary and environmental
influences. This allows us to perform
a standard IBD linkage analysis in the
DZ twins and their parents, as well as
association studies in the entire twin
cohort.
With this approach, we recently
identified a series of quantitative trait
loci (QTL) relevant to blood pressure
regulation. The strongest linkage was
found to the IGF-1 gene locus. In
collaboration with Margret Hoehe, we
have gained new insight into the
contribution of the β-2 adrenergic
receptor gene. Margret Hoehe’s team
sequenced the entire β-2 adrenergic
receptor gene in our twin cohort and
found 15 SNPs, including numerous
new mutations. Finally, we have an
active cooperation with Per Lund-
Johansen’s group in Bergen, Norway.
From the Bergen Hypertension Study,
we have genotyped offspring from
two normotensive and hypertensive
parents and have been able to
associate the Arg16->Gly variant to
blood pressure in this cohort.
We have used the QTL approach to
show that the loci for the long QTc
genes, which code for ion channels
and their regulators, are all linked to
electrocardiogram components. The
long QTc syndromes are monogenic
diseases associated with sudden
cardiac death. Showing relevance of
these genes to arrhythmias or risk of
arrhythmias in the general population,
is the first step in identifying common
variants indicating a risk to ventricular
arrhythmia. The topic is also highly
relevant to the tragic sudden infant
death (SID) syndrome. Further studies
are in progress to investigate this
issue.
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Finally, the twin studies have been
helpful in identifying a new candidate
gene for FCHL. We first looked for
linkage between the loci for the
peroxisome proliferator-activating
protein receptor (PPAR) γ gene and its
binding partner, the retinoid X
receptor (RXR) gene. The former
gene is strongly implicated in the
development of obesity. We found that
the PPAR γ gene locus is linked to
HDL cholesterol and body mass
index. Furthermore, the RXR gene
locus was strongly linked to
triglycerides. Since RXR is located
precisely at the chromosome 1q locus
linked to FCHL, RXR immediately
becomes a very attractive candidate
gene for this condition.
New perspectives
Katrin Hoffmann is studying an
isolated population in Germany,
namely the Sorbs. She has collected
60 families with hypertension and is
in the process of performing a total
genome scan in cooperation with
André Reis. Tom Lindner, who has
collected 350 sibpairs with type 2
diabetes from eastern Germany, joins
the group after a fellowship with
Graeme Bell at the University of
Chicago. He is funded to conduct
family studies involving a cohort of
dialysis patients with type 2 diabetes.
5,0
4,0
3,0
2,0
1,0
0,0
-1,0
-2,0
-3,0
D13S175
LOD
D13S217
D13S171
D13S263
D13S153
D13S1306 D13S789
D13S156
D13S795 D13S1300
D13S794
D13S265
D13S170 D13S271
Figure 18: The results of linkage analysis using
MLB and MLBQTL in the FH pedigree are
shown together with the linkage results for LDL
in the DZ twins (p values transformed into LOD
scores). In the twins, the peak level of
significance was 0.0002, right on marker
D13S1241 (Am J Hum Genet 66, 157-166,
2000).
D13S1241 D13S786
D13S129 D13S125 D13S254 D13S154
D13S159
D13S158
D13S173
LOD MLB affected sib pairs
LOD MLB QTL
LOD twins
D13S285