Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability.

Genomic copy number variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs > 50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of intelligence quotient when duplicated or deleted, respectively. Effect sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.

Estimating the effects of copy-number variants on intelligence using hierarchical Bayesian models.

It is challenging to estimate the phenotypic impact of the structural genome changes known as copy-number variations (CNVs), since there are many unique CNVs which are nonrecurrent, and most are too rare to be studied individually. In recent work, we found that CNV-aggregated genomic annotations, that is, specifically the intolerance to mutation as measured by the pLI score (probability of being loss-of-function intolerant), can be strong predictors of intellectual quotient (IQ) loss. However, this aggregation method only estimates the individual CNV effects indirectly. Here, we propose the use of hierarchical Bayesian models to directly estimate individual effects of rare CNVs on measures of intelligence. Annotation information on the impact of major mutations in genomic regions is extracted from genomic databases and used to define prior information for the approach we call HBIQ. We applied HBIQ to the analysis of CNV deletions and duplications from three datasets and identified several genomic regions containing CNVs demonstrating significant deleterious effects on IQ, some of which validate previously known associations. We also show that several CNVs were identified as deleterious by HBIQ even if they have a zero pLI score, and the converse is also true. Furthermore, we show that our new model yields higher out-of-sample concordance (78%) for predicting the consequences of carrying known recurrent CNVs compared with our previous approach.

Regulation of blood flow in adipose tissue: involvement of the cholinergic system.

Acetylcholine (Ach) has vasodilatory actions. However, data are conflicting about the role of Ach in regulating blood flow in subcutaneous adipose tissue (ATBF). This may be related to inaccurate ATBF recording or to the responder/nonresponder (R/NR) phenomenon. We showed previously that healthy individuals are R (ATBF increases postprandially by >50% of baseline BF) or NR (ATBF increases ≤50% postprandially). Our objective was to assess the role of the cholinergic system on ATBF in R and NR subjects. ATBF was manipulated by in situ microinfusion of vasoactive agents (VA) in AT and monitored by the (133)Xenon washout technique (both recognized methods) at the VA site and at the control site. We tested incrementally increasing doses of Ach (10(-5), 10(-3), and 10(-1) mol/l; n = 15) and Ach receptor antagonists (Ra) before and after oral administration of 75-g glucose using atropine (muscarinic Ra; 10(-4) mol/l, n = 13; 10(-5) mol/l, n = 22) and mecamylamine (nicotinic Ra; 10(-3) mol/l, n = 15; 10(-4) mol/l, n = 10). Compared with baseline [2.41 (1.36-2.83) ml·100 g(-1)·min(-1)], Ach increased ATBF dose dependently [3.32 (2.80-5.09), 6.46 (4.36-9.51), and 10.31 (7.98-11.52), P < 0.0001], with no difference between R and NR. Compared with control side, atropine (both concentrations) had no effect on fasting ATBF; only atropine 10(-4) mol/l decreased post-glucose ATBF [iAUC: 1.25 (0.32-2.91) vs. 1.98 (0.64-2.94); P = 0.04]. This effect was further apparent in R. Mecamylamine had no impact on fasting and postglucose ATBF in R and NR. Our results suggest that the cholinergic system is implicated in ATBF regulation, although it has no role in the blunting of ATBF response in NR.

Implementation of a "hypoglycemia kit" in a pediatric emergency room: A retrospective study during 2011-2019.

INTRODUCTION: Hypoglycemia is a common symptom in pediatrics that can lead to neurological sequelae. The etiologies are mostly benign, but hypoglycemia can be a symptom of severe underlying disease. To streamline the etiological investigations, a "hypoglycemia kit," containing supplies needed to perform specific analyses quickly, was made available in the pediatric emergency department of the Rouen University Hospital in 2011. Since its introduction, this kit has been used to explore all cases of hypoglycemia regardless of the context. However, although very useful, these analyses are expensive. The objective of our study was to examine the cost-effectiveness of this kit and to refine its indications if necessary. METHODS: This was a non-interventional and retrospective single-center study. Digital records of patients for whom a hypoglycemia kit was used from September 2011 to August 2019 at the pediatric emergency department of Rouen University Hospital were used to retrieve clinical characteristics, laboratory results, and the causes of hypoglycemia. RESULTS: The study included 82 patients. The etiologic investigation concluded that 74 patients had functional hypoglycemia, and eight cases were attributed to other etiologies. In two cases, the kit led to a diagnosis, i.e., 2.4 % efficiency. A history of congenital malformations or previous hypoglycemia was significantly associated with severe etiologies. However, there was no significant association between hypoglycemia severity, age, sex, and these etiologies. CONCLUSION: Our study reveals that the cost-effectiveness of the hypoglycemia kit is low in pediatric emergencies (2.4 %) at Rouen University Hospital, where functional hypoglycemia remains the leading cause of hypoglycemia. However, our results allow us to suggest a decision tree for refining the usability of this kit, which would considerably increase its efficiency.

Subcutaneous adipose tissue metabolism and pharmacology: a new investigative technique.

According to the Fick principle, any metabolic or hormonal exchange through a given tissue depends on the product of blood flow by arteriovenous difference. Because adipose tissue plays dual storage and endocrine roles, regulation of adipose tissue blood flow (ATBF) is of pivotal importance. Monitoring ATBF in humans can be achieved through different methodologies, such as the (133)Xe washout technique, considered to be the "gold standard", as well as microdialysis and other methods that are not well validated as of yet. This report describes a new method, called "adipose tissue microinfusion" or "ATM", which simultaneously quantifies ATBF by combining the (133)Xe washout technique together with variations of ATBF induced by local infusion of vasoactive agents. The most appropriate site for ATM investigation is the subcutaneous adipose tissue of the anterior abdominal wall. This innovative method conveniently enables the direct comparison of the effects on ATBF of any vasoactive compound, drug, or hormone against a contralateral saline control. The ATM method improves the accuracy and feasibility of physiological and pharmacological studies on the regulation of ATBF in vivo in humans.

Dose-dependent delay of the hypoglycemic effect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study.

OBJECTIVE: Injected volume and subcutaneous adipose tissue blood flow (ATBF) affect insulin absorption. Pharmacokinetics of short-acting insulin analogs were established by assessing injection of small doses in lean subjects, healthy or with type 1 diabetes. In obese patients, however, daily dosages are larger and ATBF is decreased. This study assessed the kinetics of a short-acting insulin analog in obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: Euglycemic clamps after subcutaneous lispro injections were performed. Six healthy control subjects received 10 units. Seven obese (BMI 38.3 ± 7.0 kg/m(2)) subjects with type 2 diabetes received 10, 30, and 50 units. Plasma lispro was measured by specific radioimmunoassay and ATBF by the (133)Xe-washout technique. RESULTS: ATBF was 64% lower in subjects with type 2 diabetes than in control subjects. After 10 units injection, time to lispro plasma peak (T(max)) was similar (48.3 vs. 55.7 min; control subjects versus type 2 diabetic subjects), although maximal concentration (C(max))/dose was 41% lower in subjects with type 2 diabetes, with lower and delayed maximal glucose infusion rate (GIR(max): 9.0 vs. 0.6 mg/kg/min, P < 0.0001, 69 vs. 130 min, P < 0.0001, respectively). After 30- and 50-unit injections, T(max) (88.6 and 130.0 min, respectively) and time to GIR(max) (175 and 245 min) were further delayed and dose related (r(2) = 0.51, P = 0.0004 and r(2) = 0.76, P < 0.0001, respectively). CONCLUSIONS: Absorption and hypoglycemic action of increasing dosages of lispro are critically delayed in obese subjects with type 2 diabetes.