Variant set-based association tests were performed using SKAT (Lee et al., 2012b) to identify sets of variants associated with AD symptom count. To form the sets, we used the annotations described in 2.2. Taking the POLYPHEN – Damaging annotation as an example, within a given gene, all variants that had a POLYPHEN – Damaging annotation were used to form the variant set. Those variants that did not have the annotation were not included in the set. If a set had only one variant that overlapped with a specific annotation in a given gene, then it was excluded from testing as the test would be equivalent to the individual variant test described above. By forming variant sets based on their overlap with a specific annotation, we are able to test whether variants that cause damaging amino acid changes or variants involved in regulatory processes or some other function could potentially be causal.
