A genome wide association experiment (500K) for gallstone susceptibility loci

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The disease: Gallstones represent a common and costly health problem: 10 - 15% of the population are affected and over 170,000 cholecystectomies are performed annually in Germany. 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 2-4fold 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 for common gallstone disease.State of research and own preceding work: The applicants have identified three novel risk genes for human, common gallstone disease (ABCG5/8, UGT1A1 and TM4SF4) which have been published in Nature Genetics and Gastroenterology. The applicants have assembled the world`s largest set of patient samples with gallstone disease and stone-free controls from Germany, Denmark, Chile and India (Total N>10.000).Strategy and work programme: The previous gene discoveries were achieved by a very small scan in high-risk patients (280 cases) and through “opportunistic use” of larger existing data sets, that were, however, not selected for an early onset gallstone phenotype (N=597 cases). Thus, a current generation GWAS in a larger sample of high-risk individuals is needed to detect the next genetic susceptibility variants (odds ratios 1.3 - 2) for human gallstone disease. To this end, a multi-stage multi-cohort GWAS design will be employed. A GWAS experiment comparing 1200 high-risk cases with gallstone disease (age of onset before the age of 50) against existing control genotypes (N=1200) will be performed for hypothesis generation. Validation of selected top-ranking variants will be performed in an independent German (N=1500/1500) sample. Validated variants will be subsequently replicated in Chilean (N=1500/1500), and German (N=2500/2500) patient cohorts and controls. In two replicated risk regions, the causative variants shall be better defined through the use of targeted deep sequencing. Known and novel genetic risk variants and clinical/epidemiological parameters shall be evaluated in the two comprehensively characterized population-based cohorts (SHIP, Germany, N>8500 and MONICA10, Denmark, N>2600) in order to develop a model of gene-environment interaction (G x E) for gallstone risk.