We noticed that this SNP is the most strongly associated variant at one of our six validated loci, NEGR1. To understand better common patterns of structural variation at NEGR1, we analyzed hybridization data from 270 HapMap samples, finding that two distinct genomic segments upstream of NEGR1 are copy number variable (Fig. 4b). Haplotype analysis indicated that two deletion polymorphisms—a 10-kb deletion and a 45-kb deletion—are segregating at the locus on distinct haplotypes (Fig. 4c). The two most significantly BMI-associated SNPs immediately flank the 45-kb deletion and are in perfect LD with it (r2 = 1.0) across all HapMap analysis panels. Indeed, what initially seemed to be a long associated haplotype (the 47.3 kb spanned by these SNPs on the reference genome sequence) is in fact a short haplotype whose major feature is the absence of 45.6 kb of the reference sequence (Fig. 4c). The 45-kb deletion is therefore a strong candidate to explain the association signal at NEGR1. Although the deletion region consists entirely of noncoding sequence, the deletion allele lacks several conserved elements upstream of NEGR1 that are present on the other structural haplotypes at the locus (Fig. 4c).
