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Abnormalities in sleep and circadian rhythms are central features of bipolar disorder (BP), often persisting between episodes. We report here, to our knowledge, the first systematic analysis of circadian rhythm activity in pedigrees segregating severe BP (BP-I). By analyzing actigraphy data obtained from members of 26 Costa Rican and Colombian pedigrees [136 euthymic (i.e., interepisode) BP-I individuals and 422 non-BP-I relatives], we delineated 73 phenotypes, of which 49 demonstrated significant heritability and 13 showed significant trait-like association with BP-I. All BP-I-associated traits related to activity level, with BP-I individuals consistently demonstrating lower activity levels than their non-BP-I relatives. We analyzed all 49 heritable phenotypes using genetic linkage analysis, with special emphasis on phenotypes judged to have the strongest impact on the biology underlying BP. We identified a locus for interdaily stability of activity, at a threshold exceeding genome-wide significance, on chromosome 12pter, a region that also showed pleiotropic linkage to two additional activity phenotypes. bipolar disorder | endophenotypes | circadian rhythms | actigraphy | behavior Q uantitative sleep and activity measures are hypothesized to be endophenotypes for bipolar disorder (BP). Disturbance of sleep and circadian activity typically precedes and may precipitate the initial onset of BP (1, 2). Decreased sleep and increased activity occur before and during manic and hypomanic episodes. Conversely, increased sleep and decreased activity characterize BP-depression. Extreme diurnal variation in mood features prominently in both mania and depression, whereas shifts in circadian phase (the time within the daily activity cycle at which periodic phenomena such as bed time or awakening occur) can induce mania and ameliorate symptoms of BP-depression (3).Twin studies have identified multiple heritable sleep and activity phenotypes, including sleep duration, sleep quality, phase of activity preference and sleep pattern, and sleep architecture variables [e.g., the amount of slow wave and rapid eye movement (REM) sleep (4) and polysomnography profiles during non-REM sleep (5)]. Euthymic BP individuals, compared with healthy controls, display trait-like alterations in several such phenotypesfor example, sleep time and time in bed, sleep onset latency, and periods of being awake after sleep onset (6). However, no prior investigations have assayed the heritability of such phenotypes in BP individuals and their relatives.We report here the delineation of sleep and activity BP endophenotypes through investigations of 26 pedigrees (n = 558) ascertained for severe BP (BP-I), from the genetically related populations of the Central Valley of Costa Rica (CR) and Antioquia, Colombia (CO) (7-9). Pedigrees ascertained for multiple cases of severe BP (BP-I) should be enriched for extreme values of quantitative traits that are BP endophenotypes, enhancing their utility for genetic mapping studies of such phenotypes. Additionally, su...

Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar ...