A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.Please refer to the manuscript or visit the publisher's website for funding infomation

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.Peer reviewe

Training Primary Care Physicians to Employ Self-Efficacy-Enhancing Interviewing Techniques: Randomized Controlled Trial of a Standardized Patient Intervention.

BackgroundPrimary care providers (PCPs) have few tools for enhancing patient self-efficacy, a key mediator of myriad health-influencing behaviors.ObjectiveTo examine whether brief standardized patient instructor (SPI)-delivered training increases PCPs' use of self-efficacy-enhancing interviewing techniques (SEE IT).DesignRandomized controlled trial.ParticipantsFifty-two family physicians and general internists from 12 primary care offices drawn from two health systems in Northern California.InterventionsExperimental arm PCPs received training in the use of SEE IT training during three outpatient SPI visits scheduled over a 1-month period. Control arm PCPs received a single SPI visit, during which they viewed a diabetes treatment video. All intervention visits (experimental and control) were timed to last 20&nbsp;min. SPIs portrayed patients struggling with self-care of depression and diabetes in the first 7&nbsp;min, then delivered the appropriate intervention content during the remaining 13&nbsp;min.Main measuresThe primary outcome was provider use of SEE IT (a count of ten behaviors), coded from three audio-recorded standardized patient visits at 1-3&nbsp;months, again involving depression and diabetes self-care. Two five-point scales measured physician responses to training: Value (7 items: quality, helpfulness, understandability, relevance, feasibility, planned use, care impact), and Hassle (2 items: personal hassle, flow disruption).Key resultsPre-intervention, study PCPs used a mean of 0.7 behaviors/visit, with no significant between-arm difference (P = 0.23). Post-intervention, experimental arm PCPs used more of the behaviors than controls (mean 2.7 vs. 1.0 per visit; adjusted difference 1.7, 95&nbsp;% CI 1.1-2.2; P &lt; 0.001). Experimental arm PCPs had higher training Value scores than controls (mean difference 1.05, 95&nbsp;% CI 0.68-1.42; P &lt; 0.001), and similarly low Hassle scores.ConclusionsPrimary care physicians receiving brief SPI-delivered training increased their use of SEE IT and found the training to be of value. Whether patients visiting SEE IT-trained physicians experience improved health behaviors and outcomes warrants study. CLINICALTRIALS.Gov identifierNCT01618552

Defining and evaluating a novel outcome measure representing end-stage knee osteoarthritis: data from the Osteoarthritis Initiative

OBJECTIVE: We described a definition of end-stage knee osteoarthritis (esKOA) and evaluated its association with health outcomes and osteoarthritis risk factors. METHOD: We included Osteoarthritis Initiative participants with or at-risk for knee osteoarthritis who had complete baseline data. We defined esKOA by adapting a validated appropriateness algorithm for total knee replacement based on data from baseline and the first 4 follow-up visits. We performed person-based analyses, including both knees from all participants. Participants met the definition of esKOA at the visit at which ≥1 knees reached the esKOA criteria. We assessed differences in individual characteristics between groups at baseline and over time; and tested if incident esKOA (outcome) was associated with osteoarthritis risk factors (e.g. age, maximum adult weight, quadriceps strength). RESULTS: The cohort consisted of 3916 participants with mean age of 61 (SD=9) years, and mean body mass index of 28.4 (4.7) kg/m(2); 59% were female, and 9.7% developed incident esKOA. Those with incident esKOA had poorer health outcomes at baseline and greater declines in health outcomes, with the exception of SF-12 mental health score. Five out of 9 tested risk factors were associated with incident esKOA in unadjusted analyses, with older age (≥65 years; odds ratio=1.44, 95% confidence interval=1.19 to 1.83) and quadriceps weakness (odds ratio=0.78, 95% confidence interval=0.71 to 0.86) remaining significant in adjusted models. CONCLUSIONS: Older age and quadriceps weakness predicted esKOA. esKOA is also characterized by poor health-related outcomes. This definition of esKOA could be a new clinically relevant outcome measure for osteoarthritis research

The Windsor Salt

This publication contains poetry, prose, photographs and drawings by more than 100 artists and writers from Windsor, Ontario. In their introduction Laliberte and Morin describe how the publication came into being, and suggest that the pieces presented reflect the diversity of perspectives within Windsor’s arts community. Brief biographical notes. 23 bibl. ref