Sanofi Aventis, Servier & Takeda. MS receives funding from Pfizer Inc. for a project not related to this research. IB and spouse own stock in GlaxoSmithKline and Incyte Corp. ZE and CDB currently serve on the editorial board of PLOS Genetics. AC reports personal fees from Novartis, personal fees from Thermo Fisher Scientific, personal fees from Philips, personal fees from Sanofi, personal fees from Stallergenes Greer, outside the submitted work. KC in involved in consultancy for Danone Research, LNC-therapeutic and Confo-therapeutic but no personal funding is received and this activity not linked to the present research.

No abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

The Drug Burden Index (DBI) is associated with poorer physical function in stable, community-dwelling, older people. The authors speculated that a higher DBI is associated with reduced physical function (Barthel Index, primary outcome) and predicts adverse outcomes (length of stay, in-hospital mortality, secondary outcomes) in frail, acutely ill, older hospitalized patients. Clinical and demographic characteristics, Barthel Index, DBI, and full medication exposure were recorded on admission in 362 consecutive patients (84 ± 7 years old) admitted to 2 acute geriatric units between February 1, 2010, and June 30, 2010. A unit increase in DBI was associated with a 29% reduction in the odds of being in a higher Barthel Index quartile than a lower quartile (odds ratio, 0.71; 95% confidence interval, 0.55-0.91; P = .007). The Barthel Index components mostly affected were bathing (P < .001), grooming (P < .001), dressing (P = .001), bladder function (P < .001), transfers (P = .001), mobility (P < .001), and stairs (P < .001). A higher DBI independently predicted length of stay (hazard ratio, 1.23; 95% confidence interval, 1.06-1.42; P = .005) but not in-hospital mortality (hazard ratio, 1.17; 95% confidence interval, 0.72-1.90; P = .52). Higher DBI scores on admission are independently associated with lower scores of the Barthel Index and predict length of stay among older hospitalized patients. The DBI may be useful in the acute setting to improve risk stratification.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2–18 years old) and 15 599 controls (consistently &lt;50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.