Population-based study of genetic variation in individuals with autism spectrum disorders from Croatia

<p>Abstract</p> <p>Background</p> <p>Genome-wide studies on autism spectrum disorders (ASDs) have mostly focused on large-scale population samples, but examination of rare variations in isolated populations may provide additional insights into the disease pathogenesis.</p> <p>Methods</p> <p>As a first step in the genetic analysis of ASD in Croatia, we characterized genetic variation in a sample of 103 subjects with ASD and 203 control individuals, who were genotyped using the Illumina HumanHap550 BeadChip. We analyzed the genetic diversity of the Croatian population and its relationship to other populations, the degree of relatedness via Runs of Homozygosity (ROHs), and the distribution of large (>500 Kb) copy number variations.</p> <p>Results</p> <p>Combining the Croatian cohort with several previously published populations in the FastME analysis (an alternative to Neighbor Joining) revealed that Croatian subjects cluster, as expected, with Southern Europeans; in addition, individuals from the same geographic region within Europe cluster together. Whereas Croatian subjects could be separated from a sample of healthy control subjects of European origin from North America, Croatian ASD cases and controls are well mixed. A comparison of runs of homozygosity indicated that the number and the median length of regions of homozygosity are higher for ASD subjects than for controls (p = 6 × 10^-3). Furthermore, analysis of copy number variants found a higher frequency of large chromosomal rearrangements (>2 Mb) in ASD cases (5/103) than in ethnically matched control subjects (1/197, p = 0.019).</p> <p>Conclusions</p> <p>Our findings illustrate the remarkable utility of high-density genotype data for subjects from a limited geographic area in dissecting genetic heterogeneity with respect to population and disease related variation.</p

The benefit of directly comparing autism and schizophrenia for revealing mechanisms of social cognitive impairment

Autism and schizophrenia share a history of diagnostic conflation that was not definitively resolved until the publication of the DSM-III in 1980. Though now recognized as heterogeneous disorders with distinct developmental trajectories and dissociative features, much of the early nosological confusion stemmed from apparent overlap in certain areas of social dysfunction. In more recent years, separate but substantial literatures have accumulated for autism and schizophrenia demonstrating that abnormalities in social cognition directly contribute to the characteristic social deficits of both disorders. The current paper argues that direct comparison of social cognitive impairment can highlight shared and divergent mechanisms underlying pathways to social dysfunction, a process that can provide significant clinical benefit by informing the development of tailored treatment efforts. Thus, while the history of diagnostic conflation between autism and schizophrenia may have originated in similarities in social dysfunction, the goal of direct comparisons is not to conflate them once again but rather to reveal distinctions that illuminate disorder-specific mechanisms and pathways that contribute to social cognitive impairment

Low serum osteoprotegerin levels in normoalbuminuric type 1 diabetes mellitus

“The original publication is available at www.springerlink.com”. Copyright Springer [Full text of this article is not available in the UHRA]The aim of this study is to establish whether abnormal mineral metabolism is present in patients with type 1 DM with normal renal function and in the absence of microalbuminuria. Serum levels of 1,25-dihydroxyvitamin D, osteoprotegerin (OPG) and receptor activator for nuclear factor kappa β ligand (RANKL) and other determinants of bone metabolism were measured in 35 patients with type 1 DM and in 25 age-, sex- and ethnicity-matched healthy controls. Serum OPG (1.98 vs. 2.98 pmol/l: P = 0.001), 1,25-dihydroxyvitamin D (41.1 vs. 48.2 pmol/l: P = 0.035) and magnesium (0.84 vs. 0.89 mmol/l P = 0.029) levels were significantly lower in patients with type 1 DM compared to normal controls. RANKL levels were similar in both groups. The groups did not differ with respect to calcium, phosphate, PTH, 25-hydroxyvitamin D, tubular reabsorption of phosphate and cross-linked N-telopeptides of type 1-collagen levels. Abnormalities of mineral metabolism including low serum OPG and 1,25-dihydroxyvitamin D levels occur in patients with type 1 DM with normal renal function and in the absence of microalbuminuria. These abnormalities may promote altered bone metabolism and vascular pathology.Peer reviewe

Early life infection alters adult BALB/c hippocampal gene expression in a sex specific manner

During the perinatal period, the developing brain is sensitive to environmental events. Deleterious programing resulting from infection, dietary restriction, or psychological stress has been observed and affects adult immune and endocrine systems as well as behavior. In this study, we determined whether neonatal infection permanently alters immune and glucocorticoid receptor signaling pathways in the adult hippocampus. A Chlamydia muridarum respiratory infection was induced in male and female mice at birth. Mice were allowed to recover and microarray analysis was conducted on RNA from adult hippocampal tissue. In males, neonatal infection induced an up-regulation of genes associated with cellular development, nervous system development and function, such as cyclin-dependent kinase inhibitor 1A. After neonatal infection, adult females exhibited a T-helper 2 immune bias with genes such as major histocompatibility complex, class II, DQ beta 1 up-regulated. Expression of prolactin, vasopressin, hypocretin, corticotrophin-releasing hormone-binding protein, and oxytocin were confirmed by quantitative real-time polymerase chain reaction. This study shows that neonatal infection differentially alters the gene expression profiles of both female and male mice along immune and neuroendocrine pathways.O. Wynne, J. C. Horvat, A. Osei-Kumah, R. Smith, P. M. Hansbro, V. L. Clifton & D. M. Hodgso