The Number of Genomic Copies at the 16p11.2 Locus Modulates Language, Verbal Memory, and Inhibition.

Deletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported. This study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects. IQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs. The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Heating produced by therapeutic ultrasound in the presence of a metal plate in the femur of canine cadavers

The present study aimed to assess the heat generated by a therapeutic ultrasound (TUS) in a metal bone plate and adjacent structures after fixation to the femur of canine cadavers. Ten pairs of hind limbs were used, and they were equally distributed between groups that were subjected to 1- and 3-MHz frequencies, with each frequency testing 1- and 2-W/cm² intensities. The right hind limb was defined as the control group (absence of the metal plate), and the left hind limb was the test group (presence of the metal plate). Therefore, the control groups (CG) were denominated CGI, using TUS with 1-MHz frequency and 1-W/cm² intensity; CGII, using 1-MHz frequency and 2-W/cm² intensity; CGIII, using 3-MHz frequency and 1-W/cm² intensity; and CGIV, using 3-MHz frequency and 2-W/cm² intensity. For each control group, its respective test group (TG) was denominated TGI, TGII, TGIII and TGIV. The TUS was applied to the lateral aspect of the thigh using the continuous mode and a 3.5-cm² transducer in a 6.25-cm² area for 2 minutes. Sensors were coupled to digital thermometers that measured the temperature in different sites before (t0) and after (t1) of the TUS application. The temperatures in t1 were higher in all tested groups. The intramuscular temperature was significantly higher (P<0.05) in the groups used to test the 3-MHz frequency in the presence of the metal plate. The therapeutic ultrasound in the continuous mode using frequencies of 1 and 3 MHz and intensities of 1 and 2 W/cm2 for 2 minutes caused heating of the metal plate and adjacent structures after fixation to the femur of canine cadavers

Immediate physical therapy in dogs with rupture of the cranial cruciate ligament submitted to extracapsular surgical stabilization

The study evaluated the influence of immediate physical therapy on the functional recovery of hind limbs of dogs with experimental cranial cruciate ligament rupture which underwent surgical extracapsular stabilization as well as to verify its interference in joint stability. Eight dogs were randomly divided into two groups: GI (control) (n=4) and GII (physical therapy) (n=4). The dogs in GII underwent the following therapeutic treatments in the postoperative period: cryotherapy, passive joint movement, massage, passive straightening, neuromuscular electrical stimulation, hydrotherapy (bath and aquatic mat) and therapeutic exercises. We performed evaluations of the thigh circumference, goniometry, X-ray, and knee stability (drawer test). Results did not demonstrate a significant difference between the groups nor between different post-operative times. Regarding gait analysis, we found that the 4 dogs in GI remained in degree 3 of lameness 45 and 90 days postoperatively. However, in GII, one dog remained in degree 3 45 and 90 days after surgery; one dog changed from degree 3 to 4 90 days after surgery and the other 2 dogs changed from degree 3 to 5 90 days after surgery. It is possible to conclude that dogs with CCL rupture that undergo immediate physical therapy demonstrate better results in regards to functional gait recovery. The therapeutic modalities used in the immediate post-operative period did not cause instability of the operated knee. Further studies are needed with a larger number of dogs to indicate the immediate physical therapy in dogs with CCL ligament rupture which underwent extracapsular stabilization