Aim 6 (rare variation) will systematically evaluate ~100 large pedigrees to search for genetic variants of large effect. We have engaged the large network of PGC clinicians in this task. Most experienced clinicians have encountered unusual pedigrees with high concentrations of severe psychiatric disorders. For example, one pedigree has >100 individuals with a severe psychiatric disorder and eight pedigrees have ≥20 affected individuals. Other pedigrees are from genetic isolates where interpedigree marriage is common. Still other pedigrees have extensive comorbidity with intellectual disability and epilepsy. No one has systematically and comprehensively evaluated a large collection of densely affected pedigrees using comprehensive genomic assays (karyotyping, identity-by-descent, CNVs, whole genome sequencing, and GRS) combined with a rigorous statistical framework. However, a pedigree very dense with psychiatric disorders can occur because a rare variant of strong effect is segregating in that pedigree or because that pedigree has an unusually high number of common variants of small effect (see reference (51) for an example).
