A resource of induced pluripotent stem cell (iPSC) lines including clinical, genomic, and cellular data from genetically isolated families with mood and psychotic disorders.

Genome-wide (GWAS) and copy number variant (CNV) association studies have reproducibly identified numerous risk alleles associated with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ), but biological characterization of these alleles lags gene discovery, owing to the inaccessibility of live human brain cells and inadequate animal models for human psychiatric conditions. Human-derived induced pluripotent stem cells (iPSCs) provide a renewable cellular reagent that can be differentiated into living, disease-relevant cells and 3D brain organoids carrying the full complement of genetic variants present in the donor germline. Experimental studies of iPSC-derived cells allow functional characterization of risk alleles, establishment of causal relationships between genes and neurobiology, and screening for novel therapeutics. Here we report the creation and availability of an iPSC resource comprising clinical, genomic, and cellular data obtained from genetically isolated families with BD and related conditions. Results from the first 324 study participants, 61 of whom have validated pluripotent clones, show enrichment of rare single nucleotide variants and CNVs overlapping many known risk genes and pathogenic CNVs. This growing iPSC resource is available to scientists pursuing functional genomic studies of BD and related conditions.

The genetics of bipolar disorder.

Bipolar disorder (BD) is one of the most heritable mental illnesses, but the elucidation of its genetic basis has proven to be a very challenging endeavor. Genome-Wide Association Studies (GWAS) have transformed our understanding of BD, providing the first reproducible evidence of specific genetic markers and a highly polygenic architecture that overlaps with that of schizophrenia, major depression, and other disorders. Individual GWAS markers appear to confer little risk, but common variants together account for about 25% of the heritability of BD. A few higher-risk associations have also been identified, such as a rare copy number variant on chromosome 16p11.2. Large scale next-generation sequencing studies are actively searching for other alleles that confer substantial risk. As our understanding of the genetics of BD improves, there is growing optimism that some clear biological pathways will emerge, providing a basis for future studies aimed at molecular diagnosis and novel therapeutics.