Samoans are a unique founder population with a high prevalence of obesity1–3, making them well suited for identifying new genetic contributors to obesity4. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10−14), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10−9). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10−20). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36–1.45 kg/m2 per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a ‘thrifty’ variant hypothesis as a factor in human obesity.

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Background: Batch effects in DNA methylation microarray experiments can lead to spurious results if not properly handled during the plating of samples.Methods: Two pilot studies examining the association of DNA methylation patterns across the genome with obesity in Samoan men were investigated for chip- and row-specific batch effects. For each study, the DNA of 46 obese men and 46 lean men were assayed using Illumina's Infinium HumanMethylation450 BeadChip. In the first study (Sample One), samples from obese and lean subjects were examined on separate chips. In the second study (Sample Two), the samples were balanced on the chips by lean/obese status, age group, and census region. We used methylumi, watermelon, and limma R packages, as well as ComBat, to analyze the data. Principal component analysis and linear regression were, respectively, employed to identify the top principal components and to test for their association with the batches and lean/obese status. To identify differentially methylated positions (DMPs) between obese and lean males at each locus, we used a moderated t-test.Results: Chip effects were effectively removed from Sample Two but not Sample One. In addition, dramatic differences were observed between the two sets of DMP results. After “removing” batch effects with ComBat, Sample One had 94,191 probes differentially methylated at a q-value threshold of 0.05 while Sample Two had zero differentially methylated probes. The disparate results from Sample One and Sample Two likely arise due to the confounding of lean/obese status with chip and row batch effects.Conclusion: Even the best possible statistical adjustments for batch effects may not completely remove them. Proper study design is vital for guarding against spurious findings due to such effects.

Objective To examine the additive effect of age on disability for adults with SCI. Design Prospective cohort study. Setting Spinal Cord Injury Model Systems. Participants The study sample individuals with SCI with a discharge motor-FIM score and at least one follow-up motor-FIM score who also provided measures of other covariates (N=1,660). Seventy-nine percent of the sample was male, 72% was white, 16% had paraplegia, incomplete; 33.0% had paraplegia, complete; 30% had tetraplegia, incomplete; and 21% had tetraplegia, complete. The participants’ median age at injury was 32 years (range, 6–88). Main Outcome Measures The primary study outcome was the motor subscale of the Functional Independence Measure (motor-FIM). We used a mixed models approach to examine the additive effect of age on disability for individuals with SCI. Results When controlling for motor-FIM at discharge from rehabilitation, level and severity of injury, age at injury, gender, and race, the Age × Time interaction was not significant (p=0.07). Age at SCI was significantly associated with motor-FIM (F1,238=22.49, p<0.0001). Two sensitivity analyses found significant interactions for both Age × Time (p=0.03; p=0.02) and Age × Time2 (p=0.01; p=0.006) models. Trajectory of motor-FIM scores are moderated slightly by age at the time of injury. The older participants were at time of injury, the greater curvature and more rapid decline was found in later years. Conclusions These findings indicate that age moderately influences disability for some individuals with SCI, and the older one is upon injury the greater the influence age has on disability. They serve as an important empirical foundation for the evaluation and development of interventions designed to augment accelerated aging experienced by individuals with SCI.