To assess the impact of different distribution cutpoints on genetic variants associated with the extremes, we chose to evaluate the 5% tails of the distribution and clinical classes of obesity, specifically obesity classes II and III. Although others have ascertained extremes differently, all variants associated with obesity-related traits in our meta-analysis were found to have directionally consistent results in five independent studies of extremely obese samples. Of the 13 loci previously identified as associated with extreme obesity,14-16,22-26 nearly all (except PCSK1 rs6232 and MAF) showed a consistent direction of effect for the tails of BMI. Only two loci (MAF and KCNMA1), originally identified for early-onset and morbid adult obesity,14,26 failed to replicate for any of our BMI-related outcomes. While it is possible that we had insufficient power if there was a substantial winner’s curse present in the initial publications, it is also conceivable that these susceptibility loci are population-specific, only contribute to risk at younger ages,47 represent false positive findings, or tag rare causal variants that are difficult to detect in population-based samples.
