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Watch out! This book will scramble your eyeballs and boggle your brain with Perplexing Puzzles, Impossible Illusions, Loopy Lines, and more dizzying delights!-- Source other than Library of Congress.

Many countries lack resources to identify patients at risk of developing Type 2 diabetes mellitus (diabetes). We aimed to develop and validate a diabetes risk score based on easily accessible clinical data. Prospective study including 5277 participants (55.0% women, 51.8±10.5 years) free of diabetes at baseline. Comparison with two other published diabetes risk scores (Balkau and Kahn clinical, respectively 5 and 8 variables) and validation on three cohorts (Europe, Iran and Mexico) was performed. After a mean follow-up of 10.9 years, 405 participants (7.7%) developed diabetes. Our score was based on age, gender, waist circumference, diabetes family history, hypertension and physical activity. The area under the curve (AUC) was 0.772 for our score, vs. 0.748 (p<0.001) and 0.774 (p = 0.668) for the other two. Using a 13-point threshold, sensitivity, specificity, positive and negative predictive values (95% CI) of our score were 60.5 (55.5-65.3), 77.1 (75.8-78.2), 18.0 (16.0-20.1) and 95.9 (95.2-96.5) percent, respectively. Our score performed equally well or better than the other two in the Iranian [AUC 0.542 vs. 0.564 (p = 0.476) and 0.513 (p = 0.300)] and Mexican [AUC 0.791 vs. 0.672 (p<0.001) and 0.778 (p = 0.575)] cohorts. In the European cohort, it performed similarly to the Balkau score but worse than the Kahn clinical [AUC 0.788 vs. 0.793 (p = 0.091) and 0.816 (p<0.001)]. Diagnostic capacity of our score was better than the Balkau score and comparable to the Kahn clinical one. Our clinically-based score shows encouraging results compared to other scores and can be used in populations with differing diabetes prevalence.

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II A muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention. Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

Genomic balance: underweight as a mirror image of obesity Underweight and obese phenotypes can both pose health risks. But whereas obesity has been associated with a number of genetic variants, little is known about the genetic basis of underweight. A large-scale screen of data from 28 cytogenetic centres in Europe and North America now shows that being underweight is frequently associated with duplication of a short region on chromosome 16. Deletion of this same chromosomal region has previously been associated with obesity. The observed associated phenotypes are opposites, or mirrors, of those reported in carriers of deletions at this locus, and correlate with changes in transcript levels for genes within the duplication but not within the adjacent regions. The suggestion is that severe obesity and being underweight could have mirror etiologies, possibly through contrasting effects on energy balance. Both obesity and being underweight have been associated with increased mortality 1 , 2 . Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m 2 in adults and ≤ −2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive 3 , 4 , 5 , feeding and eating disorder and/or anorexia nervosa 6 , 7 . In contrast to obesity, few genetic variants underlying these clinical conditions have been reported 8 , 9 . We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities 10 . Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3ml/min per 1.73m2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10-8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10-19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10-8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10-6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10-3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.