Interestingly, some loci showed significant association with traits in the opposite direction than expected based on their phenotypic correlation with BMI (Extended Data Fig. 5). For example, at HHIP, the BMI-increasing allele is associated with decreased type 2 diabetes risk and higher high-density lipoprotein cholesterol (HDL). At LOC646736 and IRS1, the BMI-increasing allele is associated with reduced risk of coronary artery disease (CAD) and diabetic nephropathy, decreased triglyceride levels, increased HDL, higher adiponectin, and lower fasting insulin. This may be due to increased subcutaneous fat and possible production of metabolic mediators protective against the development of metabolic disease despite increased adiposity8. These unexpected associations may help us to understand better the complex pathophysiology underlying these traits, and may indicate benefits or side effects if these regions contain targets of therapeutic intervention. Furthermore, of our 97 GWS loci, 35 (binomial P = 0.0019) were in high LD (r2 > 0.7) with one or more GWS SNPs in the National Human Genome Research Institute (NHGRI) GWAS catalogue (P < 5 × 10−8), even after removing anthropometric trait-associated SNPs. These SNPs were associated
