@article {Liley037713, author = {James Liley and John A Todd and Chris Wallace}, title = {A genetic test for differential causative pathology in disease subgroups}, elocation-id = {037713}, year = {2016}, doi = {10.1101/037713}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Many common diseases show wide phenotypic variation. We present a statistical method for determining whether phenotypically defined subgroups of disease cases represent different genetic pathophysiologies, in which disease-associated variants have different effect sizes in the two subgroups. Our method models the genome-wide distributions of genetic association statistics with mixture Gaussians. We apply a global test without requiring explicit identification of disease-associated variants, thus maximising power in comparison to a standard variant by variant subgroup analysis. Where evidence for genetic subgrouping is found, we present methods for post-hoc identification of the contributing genetic variants.We demonstrate the method on a range of simulated and test datasets where expected results are already known. We investigate subgroups of type 1 diabetes (T1D) cases defined by autoantibody positivity, establishing evidence for differential genetic basis with thyroid peroxidase antibody positivity, driven generally by variants in known T1D associated regions.}, URL = {https://www.biorxiv.org/content/early/2016/08/02/037713}, eprint = {https://www.biorxiv.org/content/early/2016/08/02/037713.full.pdf}, journal = {bioRxiv} }