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Schizophrenia (SZ) and Bipolar Disorder (BP) are debilitating neuropsychiatric disorders, each affecting 0.5–1% of the world's population, and for which a shared polygenic liability has been demonstrated. Here, we consider recent progress in an ongoing, Whole Genome Sequencing (WGS) study of multiply affected SZ and BP families from the Portuguese archipelagos of the Azores and Madeira. Using the Illumina HiSeq. 2000 platform, we obtained deep, WGS data (~30X) for 51 SCZ and 39 BP cases, and 72 unaffected relatives from 40 families; an additional 16 relatives meeting criteria for some other psychiatric diagnosis (e.g., major depression or alcoholism) and 7 of unknown phenotype; and 30 unrelated ethnically-matched controls. We applied a prioritization strategy for filtering putatively functional SNPs and INDELs, based on population frequency and sharing between affected relatives. We identified a disruptive INDEL in SERPINA1 carried by affected members of 10 families, and a disruptive INDEL in PCDHGA9 shared between all affected relatives in a pedigree which contributed substantially to a published linkage finding at 5q31-34. Individual burden scores of rare disruptive variants are markedly greater among affected subjects (P=0.00076) and their unaffected relatives (P=0.00034). Next, we compared lists of genes carrying family-specific variants shared among affected relatives to curated, etiologically relevant gene-sets. Following correction for multiple tests, we observed a significant overlap of genes carrying disruptive or non-synonymous variants in the PIC with genes enriched for de novo non-synonymous variants (P=5.9E-5), associated SCZ GWAS intervals (P=3.48E-4), and human post-synaptic density genes (P=9.14E-4). Genes with disruptive or non-synonymous variants also exhibited significant overlap with de novo findings for autism and intellectual disability, autism PPI networks, and FMRP targets. We demonstrate the polygenic enrichment of rare, disruptive variants in multiply-affected families from a geographically isolated archipelago. This recapitulates the pattern of results observed for common polygenic risk scores constructed from population-based GWAS, for which the comparisons of affected and unaffected relatives to controls were also significant (P=0.01 and P=0.02, respectively). Ongoing analyses include prioritization of variants leveraged by observed population structure of these geographically isolated island populations, and attempted replication of prioritized variants an independent sample of 220 SZ cases and 185 controls from the Genomic Psychiatry Cohort (GPC). [ABSTRACT FROM AUTHOR]