Both empirical16 and theoretical work29 has shown that genetic architecture may differ, the more extreme the selection, suggesting that the ascertainment strategy may impact observed results.31 To evaluate impact of ascertainment strategy, we also performed in silico look-ups of all SNPs we found to be associated with BMI-related traits in five studies that applied other ascertainment strategies for defining extremely obese (Supplementary Tables 2-5, bottom panel; total ncases=6,848; ncontrols=7,023). Four studies recruited participants from specialized clinics or hospitals based on absolute or percentile-derived cutoffs, and one study utilized liability-based (women) and standard-based (men) percentile cut-points. We performed a meta-analysis of these five studies and observed directionally consistent associations for all BMI-associated SNPs (Supplementary Table 10). The effect sizes in these extreme obesity studies were similar to those observed for tails of BMI in our analysis (Pheterogeneity>0.007 for all SNPs, Bonferroni-corrected). Four out of seven novel obesity-related loci displayed significance at P<0.007 (Bonferroni-corrected) in these extremely obese studies.
