Strong Genetic Overlaps Between Dimensional and Categorical Models of Bipolar Disorders in a Family Sample.

Background: Bipolar disorder (BD) presents with a wide range of symptoms that vary among relatives, casting doubt on categorical illness models. To address this uncertainly, we investigated the heritability and genetic relationships between categorical and dimensional models of BD in a family sample. Methods: Participants in the Amish-Mennonite Bipolar Genetics (AMBiGen) study were assigned categorical mood disorder diagnoses by structured psychiatric interview and completed the Mood Disorder Questionnaire (MDQ), which assesses lifetime history of manic symptoms and associated impairment. Major MDQ dimensions were analyzed by Principal Component Analysis (PCA) in 726 participants. Heritability and genetic overlaps between categorical diagnoses and MDQ-derived dimensions were estimated with SOLAR-ECLIPSE within 432 genotyped participants. Results: MDQ scores were significantly higher among individuals diagnosed with BD and related disorders, as expected, but varied widely among relatives. PCA suggested a three-component model for the MDQ. Heritability of the MDQ score was 30% (p<0.001), evenly distributed across its three principal components. Strong and significant genetic correlations were found between categorical diagnoses and most MDQ measures. Limitations: Recruitment through probands with BD resulted in increased prevalence of BD in this sample, limiting generalizability. Unavailable genetic data reduced sample size for some analyses. Conclusion: heritability and high genetic correlations between categorical diagnoses and MDQ measures support a genetic continuity between dimensional and categorical models of BD.

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.

Validity of the Mood Disorder Questionnaire (MDQ) as a screening tool for bipolar spectrum disorders in anabaptist populations.

The Mood Disorder Questionnaire (MDQ) is an established screening tool for bipolar spectrum disorders (BSD), but has not been validated in diverse populations and the best scoring method remains uncertain. This study assessed diagnostic validity of the MDQ among Anabaptists, an underserved population frequently involved in genetic research. 161 participants completed the MDQ and were diagnosed by a best-estimate final diagnosis (BEFD). Diagnostic agreements between alternate MDQ scoring methods and the BEFD were quantified using Cohen's Kappa (κ), sensitivity (α), and specificity (ß). Scoring criteria evaluated included >7 simultaneous symptoms and at least moderate impairment, >7 simultaneous symptoms, with at least mild impairment, >7 symptoms only, with no further requirement, and three novel scoring methods that require >5 symptoms or fewer. Diagnostic agreement varied. The original method proved most specific but had the lowest κ and sensitivity. κ increased with more liberal scoring criteria, reaching a maximum under the lower-threshold symptom methods, with little loss of specificity in the 5-symptom method. Decreasing the symptom threshold below 5 conferred little or no benefit. These results support the diagnostic validity of the MDQ among this Anabaptist sample and suggest that a 5-symptom scoring method may increase diagnostic sensitivity in populations at high risk for bipolar disorder.