Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder

Abstract

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.

Keywords: actigraphy; behavior; bipolar disorder; circadian rhythms; endophenotypes.

Fig. S1.

Example of actigraphies from one non–BP-I and one BP-I participant, from the same family. The activity level is indicated in black. The yellow line represents light levels. Dark blue bars indicate when the watch was off-wrist. Red squares below activity indicate the epochs that are scored as awake. Blue triangles indicate when the subject pressed the marker button (ideally at rest onset and rest offset). Light blue periods represent the rest period; darker light blue periods within the rest period indicate the sleep period. Rest and sleep periods were calculated by R algorithms. (A) Activity of one female non–BP-I volunteer, 59 y old, from a CO family. (B) Activity of one female BP-I volunteer, 58 y old, from the same family as A.

Fig. S2.

Flowchart representing the included and excluded subjects.

Fig. S3.

Correlation matrix among 116 variables. Darker shades of blue indicate stronger positive correlation, whereas darker shades of red indicate higher negative correlation between two variables. The 73 variables in red text were selected for further study.

Fig. 1.

Polar histogram of heritability traits and association to BP-I. The inner histogram represents the heritability estimate (h2) in yellow–green. The middle histogram represents the association to BP-I; positive associations with BP-I are presented in red (i.e., the trait has a higher value in those with BP-I), whereas negative associations are presented in blue (indicating those with BP-I have lower values on the trait). The outer histogram summarizes the heritable traits (black) and the phenotypes associated with BP-I (green). hrs, hours; mins, minutes; no., number.

Fig. S4.

Density distribution of the phenotypes found different between BP-I and non–BP-I subjects.

Fig. 2.

Representation of the multipoint LOD scores on different chromosomes (which are depicted in alternating violet and black) for 13 traits that we considered of highest biological significance. Blue line indicates an LOD score of 3.3, corresponding to a P value of 5 × 10⁻⁵. Mins, minutes; no., number.

Fig. 3.

Multipoint linkage analysis across all 49 heritable phenotypes. Chromosomes are represented in alternating colors (light gray–dark gray).

Fig. 4.

Multipoint linkage analysis of the most biological significant phenotypes; depiction of the region of pleiotropic linkage on chromosome 12p. no., number.

Fig. S5.

Example of phenotypes extracted during rest, sleep, and activity. Dark columns are activity epochs; yellow curve represents light counts. Red represents epochs scored as awake. Blue triangles indicate the epoch when the marker button was pressed by the subject to indicate bed time (rest onset and offset). Green bars represent the time that the subject indicated in the sleep log for rest onset or offset. Rest onset and offset (light blue bars), sleep onset and offset (blue bars), and midsleep time (dashed blue bars) were computed by a script in R, as described in Methods. Sleep onset latency is the time between rest onset and sleep onset. Sleep inertia is the time between sleep offset and rest offset. Examples of measurements of phase are the time of rest and sleep onset and offset and midsleep. Examples of measurement of entrainment, or fragmentation, are the sleep and awake bouts.

Fig. S6.

Activity fitting curves. (A) Cosinor and Hill transformation fitting curve. The gray curves represent the average of the hourly activity in different days of recording. The black dashed curve is the mean of the hourly average curves. Dark green solid curve represents the cosinor fitting curve on the mean of the hourly average of activity, whereas the light green solid curve is the square transformation of the cosine curve Hill transformation. The estimate of Hill Acrophase is indicated by the arrow. (B) Fourier fitting curve. Circles are the average activity of the n-th minute. Dark purple curve is the Fourier fitting curve on the activity. The curve is given by the sum of nine functions: constant (light purple), four sine curves (1–4, in green, with period of 24 h, 12 h, 6 h, and 3 h respectively), and four cosine curves (1–4, in blue, with period of 24 h, 12 h, 6 h, and 3 h, respectively).