A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd

Mice Deficient of Glutamatergic Signaling from Intrinsically Photosensitive Retinal Ganglion Cells Exhibit Abnormal Circadian Photoentrainment

<div><p>Several aspects of behavior and physiology, such as sleep and wakefulness, blood pressure, body temperature, and hormone secretion exhibit daily oscillations known as circadian rhythms. These circadian rhythms are orchestrated by an intrinsic biological clock in the suprachiasmatic nuclei (SCN) of the hypothalamus which is adjusted to the daily environmental cycles of day and night by the process of photoentrainment. In mammals, the neuronal signal for photoentrainment arises from a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) that send a direct projection to the SCN. ipRGCs also mediate other non-image-forming (NIF) visual responses such as negative masking of locomotor activity by light, and the pupillary light reflex (PLR) via co-release of neurotransmitters glutamate and pituitary adenylate cyclase-activating peptide (PACAP) from their synaptic terminals. The relative contribution of each neurotransmitter system for the circadian photoentrainment and other NIF visual responses is still unresolved. We investigated the role of glutamatergic neurotransmission for circadian photoentrainment and NIF behaviors by selective ablation of ipRGC glutamatergic synaptic transmission in mice. Mutant mice displayed delayed re-entrainment to a 6 h phase shift (advance or delay) in the light cycle and incomplete photoentrainment in a symmetrical skeleton photoperiod regimen (1 h light pulses between 11 h dark periods). Circadian rhythmicity in constant darkness also was reduced in some mutant mice. Other NIF responses such as the PLR and negative masking responses to light were also partially attenuated. Overall, these results suggest that glutamate from ipRGCs drives circadian photoentrainment and negative masking responses to light.</p></div

Influence of Music on the Stress Response in Patients Receiving Mechanical Ventilatory Support: A Pilot Study

• Background Music is considered an ideal therapy for reducing stress in patients receiving mechanical ventilation. Previous studies of the effect of music on stress in such patients have focused solely on indirect markers of the stress response rather than on serum biomarkers. • Objective To explore the influence of music on serum biomarkers of the stress response in patients receiving ventilatory support. • Methods A convenience sample of 10 patients receiving mechanical ventilation was recruited from an 11-bed medical intensive care unit. Patients were randomly assigned to listen to music or to rest quietly for 60 minutes. Levels of corticotropin, cortisol, epinephrine, and norepinephrine were measured 4 times during the 60 minutes. • Results The levels of the 4 biomarkers of the stress response did not differ significantly between patients who listened to music and patients who rested quietly, though the levels of corticotropin and cortisol showed interesting trends. • Conclusions Additional research is needed with a larger sample size to evaluate further the influence of music on biochemical markers of the stress response in patients receiving mechanical ventilatory support. In future studies, confounding factors such as endotracheal suctioning and administration of medications that influence the stress response should be controlled for

Attenuated PLRs in Vglut2-cKO mice.

<p>(A) Images of control and Vglut2-CKO mice pupils before and during exposure to high intensity (3.8 mW/cm²⁾ white light stimuli. (B) Summary of PLRs measured in control mice. Consensual PLRs were measured in control (n = 8) and Vglut2-cKO (n = 10) mice. Vglut2-cKO mice show severe deficits in PLRs under low (4 µW/cm²⁾ and high (3.8 mW/cm²⁾ intensity white light stimuli (** p<0.05). Light stimuli were delivered for 20 s and maximum pupil area was measured before and during the light stimulus. Percent of pupil area following the light stimulus is shown normalized to the pupil area during dark conditions.</p

Ablation of VGLUT2 expression in Vglut2-cKO mouse retinas.

<p>(A) Diagram of gene targeting strategy. Mouse with exon 2 of <i>Vglut2</i> gene flanked by LoxP sites was bred with the Opn4-Cre mouse line in which Cre was inserted in the Opn4 gene locus. Progeny contained mice with deletion of Vglut2 exon 2 in ipRGCs (Vglut2-cKO mice). (B) Retinal sections of Vglut2-cKO and control littermate stained for Opn4, VGLUT2. Notice the co-localization of VGLUT2 with Opn 4 (arrows) in the control but not in the Vglut2-cKO mice retinas. ONL, outer nuclear layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. Scale bar  = 50 µm.</p