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

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.

Pallidum and lateral ventricle volume enlargement in autism spectrum disorder.

Studies on structural brain abnormalities in individuals with autism spectrum disorders (ASD) have been of limited size and many findings have not been replicated. In the largest ASD brain morphology study to date, we compared subcortical, total brain (TBV), and intracranial (ICV) volumes between 472 subjects with DSM-IV ASD diagnoses and 538 healthy volunteers (age range: 6-64 years), obtained from high-resolution structural brain scans provided by the Autism Brain Imaging Data Exchange (ABIDE). Compared to healthy volunteers, we found significantly larger pallidum (Cohen's d=0.15) and lateral ventricle volumes (Cohen's d=0.18) in ASD. These enlargements were independent of total brain volume and IQ, passed FDR correction for multiple comparisons, and were observed in overall, male-only, and medication-free subjects. In addition, intracranial, hippocampal, and caudate volumes were enlarged in ASD at a nominal statistical threshold of p<0.05. This study provides the first robust evidence for pallidum enlargement in ASD independent from TBV and encourages further study of the functional role of the pallidum in individuals with autism spectrum disorder.

Heritability of Hippocampal Formation Sub-region Volumes.

BACKGROUND: Hippocampal formation (HF) volume and episodic memory performance are substantially heritable, but HF subregion heritability estimates and their possible shared genetic variance with episodic memory performance remain to be determined. METHODS AND FINDINGS: This study provides heritability estimates for hippocampal subregions (e.g, Cornu Amonis, Subiculum, Parasubiculum, Molecular and Granule Cell Layers of the Dentate Gryus) and Total HF volumes obtained using FreeSurfer 6.0. In addition, this study assesses the heritability of object sequence and verbal episodic memory performance, and the amount of shared genetic variance between HF subregions and Total HF volume and episodic memory performance. HF volumes were obtained from high-resolution brain scans from a sample of 499 siblings (mean age±SD=30.0±3.1, 203 men), including 51 monozygotic and 46 dizygotic twin pairs and 305 non-twin siblings, collected by the Human Connectome Project (www.humanconnectome.org). Heritability estimates for HF subregions ranged from 0.42-0.87 and shared genetic variance of HF subregions with hippocampal volume was substantial (mean=0.79, range=0.50-0.98). HF subregion volumes residualized for Total HF and percent HF subregion volumes were also found to be substantially heritable (range=0.04-0.86 and 0.07-0.84, respectively). Verbal (h2=0.47) but not object sequence episodic memory was found to be significantly heritable; though the amount of shared genetic variance between HF subregions and verbal episodic memory was low (mean=0.10, range=0.01-0.20). CONCLUSIONS: These findings suggest that HF subregion volumes are heritable and can be used as quantitative phenotypes in genetic association studies. The low shared genetic variance between HF subregions and verbal episodic memory suggests that quantitative trait analyses may not benefit from including both HF volume and episodic memory as bivariate traits in healthy individuals. The extent to which HF subregion volumes share genetic variance with neuropsychiatric disorders, and as such add value to our ability to identify genetic risk loci for these disorders, remains to be determined.