The traditional definition of an endophenotype requires that cases show differences from controls but also that the genetic relatives of cases show differences from controls, in essence a requirement that the endophenotype have a genetic basis. One strength of the present study is that we were able to use a large number of known schizophrenia risk variants to rank individuals according to their genetic risk for schizophrenia in multiple ways. (1) For each of the PGC variants, we tested whether the schizophrenia risk allele was also associated with any of our endophenotypes. (2) We used a polygenic risk score to obtain a weighted sum of the number of risk alleles that each participant harbored. Ultimately, this procedure rank-ordered each individual in our sample according to their genetic risk for schizophrenia, and we correlated this rank ordering with each of the endophenotypes. While these results do not rule out the possibility that these endophenotypes share a genetic basis with schizophrenia, they do indicate that much larger sample sizes than those employed here will be required to detect such an association.
