To evaluate the relevance and necessity to account for the effects of population substructure on association studies under a case-control design in central Europe, we analysed three samples drawn from different geographic areas of Germany. Two of the three samples, POPGEN (n = 720) and SHIP (n = 709), are from north[Kiel,Schleswig-Holstein] and north-east Germany[Pomerania], respectively, and one sample, KORA (n = 730), is from southern Germany[Augsburg, western Bavaria].

Population genetic differentiation was measured by classical F-statistics for different marker sets, either consisting of genome-wide selected coding SNPs located in functional genes, or consisting of selectively neutral SNPs from 'genomic deserts'.
Quantitative estimates of the degree of stratification were performed comparing the genomic control approach [Devlin B, Roeder K: Biometrics 1999;55:997-1004], structured association [Pritchard JK, Stephens M, Donnelly P: Genetics 2000;155:945-959] and sophisticated methods like random forests [Breiman L: Machine Learning 2001;45:5-32].

F-statistics showed that there exists a low genetic differentiation between the samples along a north-south gradient within Germany (F(ST)(KORA/POPGEN): 0.00017; F(ST)(KORA/SHIP): 0.00054; F(ST)(POPGEN/SHIP): 0.000013.




Instead, we could show that F ST values, despite being small, were significant for the geographically most distant populations KORA and SHIP. However, between KORA and POPGEN the difference was small and not significant, and finally between SHIP and POPGEN, the two populations from the northern part of Germany, there was no clear-cut indication of relevant substructure. These observations are compatible with the results of Cavalli-Sforza et al., who reported a slight degree of population differentiation along a north-south gradient within Germany, using blood group data.


The estimated F ST = 0.00054 between the most distant populations KORA[Augsburg, western Bavaria] and SHIP[Pomerania, eastern Germany] were 2–4 times lower than the F ST value between Germans and other Germanic populations (Dutch, Danish, English, Austrian, Swiss, Belgians), which range from 0.0010 for Germans and Swiss to 0.0022 for Germans and English.