A genome wide association experiment (500K) for gallstone susceptibility loci
(DFG HA3091/3-1)
The disease: Gallstones represent a frequent and costly health problem: 10 - 15% of the
population are affected and over 170,000 cholecystectomies are performed annually in
Germany. Essentially, the causal mechanisms of gallstone generation are not well
understood and thus no real treatment options outside the surgical removal of the organ
are established.
Genetic factors: There is a clear familial clustering of the disorder that was identified as
early as the 1930ies. The overall familial relative risk for affection with gallstones is 24fold increased over the general population. The applicants have shown that this risk
increases substantially to 20-60fold for patients with an early age of onset (<40) also
outside the rare cholestasis syndromes.
State of research: The genetic investigation of gallstone susceptibility in mice is
advanced: more than 20 “Lith” loci have been identified, although the actual causal
mutations remain to be identified. In contrast, the data on human common gallstone
susceptibility is limited to a few candidate gene studies.
Competitiveness and Resources: Collectively, the applicants have collected in excess of
4000 patients and 4000 sonographically gallstone-negative control individuals. This is
more than an order of magnitude above any previous consortium in this disease. Each
of the patient samples is geographically matched in itself, thus avoiding potential
problems with genetic substructure. 500K control genotypes of 350 sonographically
stone-free controls are available.
The epidemiological, genetic, technological (high-throughput genotyping) and
mechanistic expertise of the applicants has been demonstrated in several high-ranking
publications.
Aims: Identification of major susceptibility variants for common gallstone disease in
humans.
Work programme: The systematic genetic mapping program will be conducted as
follows:
 500K genome-wide association scan using 350 existing (stone-free) controls
and 400 high-risk cases (geographically matched) of which 200 cases are already
genotyped – AIM 1.
 Initial replication in three geographically matched follow-up samples (POPGEN
736/736, SHIP 736/736, ABC: 368/368) – AIM 2.
 Fine mapping in the above cohorts and identification of disease variants through
mutation detection and cDNA cloning – AIM 3.
 Population based verification of disease variants in POPGEN and SHIP cohorts.
Prospective validation of the predictive value using the 10-year SHIP follow-up – AIM
4.
 Mechanistic evaluation of up to two disease variants in vitro (allelic expression
systems, membrane transport assays, expression and regulation studies) and in vivo
(animal models) – AIM 5.