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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...

Most population isolates examined to date were founded from a single ancestral population. Consequently, there is limited knowledge about the demographic history of admixed population isolates. Here we investigate genomic diversity of recently admixed population isolates from Costa Rica and Colombia and compare their diversity to a benchmark population isolate, the Finnish. These Latin American isolates originated during the 16 th century from admixture between a few hundred European males and Amerindian females, with a limited contribution from African founders. We examine whole-genome sequence data from 449 individuals, ascertained as families to build mutigenerational pedigrees, with a mean sequencing depth of coverage of approximately 363. We find that Latin American isolates have increased genetic diversity relative to the Finnish. However, there is an increase in the amount of identity by descent (IBD) segments in the Latin American isolates relative to the Finnish. The increase in IBD segments is likely a consequence of a very recent and severe population bottleneck during the founding of the admixed population isolates. Furthermore, the proportion of the genome that falls within a long run of homozygosity (ROH) in Costa Rican and Colombian individuals is significantly greater than that in the Finnish, suggesting more recent consanguinity in the Latin American isolates relative to that seen in the Finnish. Lastly, we find that recent consanguinity increased the number of deleterious variants found in the homozygous state, which is relevant if deleterious variants are recessive. Our study suggests that there is no single genetic signature of a population isolate.

This report sheds new light on adolescent drug experiences in Panama, the five Spanish-heritage countries of Central America, and the Dominican Republic, and presents the first estimates of school-level clustering of youthful drug involvement in these seven countries. Placed in relation to school survey findings from North America and Europe, these estimates indicate lower levels of drug involvement in these seven countries of the Americas. For example, in the United States of America 70% of surveyed youths had tried alcohol and 59% had smoked tobacco. By comparison, in these seven countries, only 51% have tried alcohol and only 29% have smoked tobacco. Future research will help to clarify explanations for the observed variations across different countries of the world. In the meantime, strengthening of school-based and other prevention efforts in the seven-country PACARDO area may help these countries slow the spread of youthful drug involvement, reduce school-level clustering, and avoid the periodic epidemics of illegal drug use that have been experienced in North America.

To investigate the role of religiosity in the earliest stages of drug involvement, the authors studied recent-onset occurrence of first chances to try a drug and first actual drug use, expressed as a function of religious practice behaviors, levels of religious devotion, and religious affiliation. Based upon standardized questionnaire assessments of nationally representative samples of school-attending youths drawn in Panama, the five Spanish heritage countries of Central America, and the Dominican Republic (n = 12,797), the 1999-2000 study estimates indicate that higher levels of religious practice are inversely associated with the earliest stages of tobacco and cannabis experiences (i.e., the first chance to try and the first actual use) but not so for alcohol. To illustrate, for each unit increase in levels of religious practice behaviors, there was an associated reduced occurrence of the first chance to try tobacco (odds ratio = 0.76, 95% confidence interval: 0.62, 0.94). Occurrence of first actual use of tobacco and cannabis was not associated with levels of religious practice behaviors among youths exposed to the opportunity to try these drugs. As such, these behaviors apparently have not strengthened resistance. Rather, autarcesis may be at work, functioning to shield youths from drug exposure opportunities.