Multisystem component phenotypes of bipolar disorder for genetic investigations of extended pedigrees

Abstract

Importance: Genetic factors contribute to risk for bipolar disorder (BP), but its pathogenesis remains poorly understood. A focus on measuring multisystem quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that affect BP as well as its component phenotypes.

Objective: To identify quantitative neurocognitive, temperament-related, and neuroanatomical phenotypes that appear heritable and associated with severe BP (bipolar I disorder [BP-I]) and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk.

Design, setting, and participants: Multigenerational pedigree study in 2 closely related, genetically isolated populations: the Central Valley of Costa Rica and Antioquia, Colombia. A total of 738 individuals, all from Central Valley of Costa Rica and Antioquia pedigrees, participated; among them, 181 have BP-I.

Main outcomes and measures: Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging, and diffusion tensor imaging phenotypes.

Results: Of 169 phenotypes investigated, 126 (75%) were significantly heritable and 53 (31%) were associated with BP-I. About one-quarter of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions as well as volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture.

Conclusions and relevance: To our knowledge, this is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I association within families that is consistent with expectations from case-control studies. Together, these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder.

Figure 1. Summary of analyses of heritability and association with BP-I

The results of analyses of heritability and of association with BP-I are shown as two histograms stacked on top of each other. Inner histogram purple bars show the magnitude of the heritability estimate for each component phenotype and the blue box next to the trait name at the outer edge of the plot indicates estimates that passed the significance threshold. Outer histogram shows the magnitude of the estimated regression coefficient for the BP-I association test. In orange are positive coefficients representing traits that are higher in BP-I subjects compared to non-BP-I family members. In green are negative coefficients representing traits that are lower in BP-I subjects. A red box at the outer edge of the circle indicates traits that exceeded the significance threshold for association with BP-I. Abbreviations; PCET; Penn Conditional Exclusion Test, SST; Stop Signal Task, TONI; Test of Nonverbal Intelligence, AIM; Abstraction Inhibition and Memory test, IPCPT; Identical Pairs Continuous Performance Test, VWM; verbal working memory, CVLT; California Verbal Learning Test, WMS; Wechsler Memory Scale, BART; Balloon Analog Risk Task; TEMPS, Temperament Evaluation of Memphis, Pisa, Paris and San Diego; WASI, Wechsler Abbreviated Scale of Intelligence; SCAP, Spatial Capacity Delayed Response Test.

Figure 2. Structural neuroimaging phenotypes

Upper panel shows results of the heritability and BP-I association analyses of volumetric MRI phenotypes. The three representative T1-weighted MRI coronal images depict the results of the Freesurfer segmentation overlaid as colored masks selected to better distinguish the anatomy. Mask colors are not related to the results. The colors of the text labels indicate structures that showed significant evidence of familial aggregation (blue) and structures that were both heritable and associated with BP-I (magenta). Lower panel depicts cortical thickness phenotypes and shows the results of the heritability and BP-I association analysis for cortical gray matter thickness. Heritable cortical regions are colored in blue, BP-I-associated regions are shown in red and regions that were both heritable and associated with BP-I are colored in magenta. The medial surface is rotated upwards by 60° to provide a view of the ventral surface.

Figure 3. Network graph of correlations among phenotypes

Network representations of pairwise phenotypic correlations are drawn in the left panel and genetic correlations are shown in the right panel. All trait pairs were included in the phenotypic correlation analysis, and only pairs in which both traits were heritable were included in the genetic correlation analysis. Nodes are colored according to their assigned subdomain (see Subdomain column in eTable2 in the Supplemental). Circular nodes represent significantly heritable phenotypes and square nodes represent non-heritable phenotypes. Traits that were significantly associated with BP-I are drawn with a red border. Nodes are connected with an edge when the hypothesis of correlation=0 was rejected using FDR-controlled thresholds. Numbers on the graph correspond to Plot ID’s for phenotypes detailed in eTable2 in the Supplemental. Examples of genetically correlated traits mentioned in the main text can be seen in the right panel and include; 1) the hippocampus (#67), amygdala (#56) and surface area of the pars opercularis (#97); and 2) Stroop Color Word Test Errors (#34) with surface area measures from the inferior parietal (#87), and rostral middle frontal (#107) ROIs.