Investigation of Genetic Variation Underlying Central Obesity amongst South Asians

South Asians are 1/4 of the world’s population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of \u3e6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P\u3c5x10-8; variants showing equivocal association with WHR (P\u3c1x10-5) did not replicate at P\u3c0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P\u3c0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P\u3c1.5x10-6 or grouped by gene locus at P\u3c2.5x10−6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P\u3c5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans

Association of vitamin D with risk of type 1 2 diabetes: a Mendelian 2 randomisation study in European and Chinese adults

Background: Observational studies have reported that higher plasma 25-hydroxy vitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal. The aim of this study was to test the relevance of 25(OH)D for type 2 diabetes using genetically-instrumented differences in plasma 25(OH)D concentrations. Methods and findings: Data were available on four 25(OH)D single nucleotide polymorphisms (SNPs: n=82,464), plasma 25(OH)D concentrations (n=13,565) and cases with diabetes (n=5565) in China Kadoorie Biobank (CKB). The effects on risk of diabetes were assessed by a genetic score using two 25(OH)D synthesis SNPs (DHCR7-rs12785878 and CYP2R1-rs10741657), or the addition of SNPs affecting transport (GC/DBP-rs2282679) and catabolism (CYP24A1-rs6013897) of 25(OH)D. The CKB results were combined in a meta-analysis of 10 studies for the two synthesis SNPs (n=58,312 cases) and 7 studies for four SNPs (n=32,796 cases). Mean (SD) 25(OH)D concentration was 62 (20) nmol/L in CKB and the per allele effects of genetic scores on 25(OH)D were 2.87 (SE 0.39) for the synthesis SNPs and 3.54 (SE 0.32) for all SNPs. A 25 nmol/L higher biochemically measured 25(OH)D was associated with 9% (95%CI: 0-18%) lower risk of diabetes in CKB. In a meta-analysis of all studies, a 25 nmol/L higher genetically-instrumented 25(OH)D concentration was associated with a 14% (95%CI: 3-23%) lower risk of diabetes (p=0.01) using the two synthesis SNPs. An equivalent difference in 25(OH)D using a genetic score with four SNPs was not significantly associated with diabetes (OR 8%, 95% CI: -1-16% lower risk, p=0.07), but had some evidence of pleiotropy. A limitation of the meta-analysis was the access only to study level rather than individual level data. Conclusions: The concordant risks of diabetes for biochemically-measured and genetically-instrumented differences in 25(OH)D using synthesis SNPs provide evidence for a causal effect of higher 25(OH)D for prevention of diabetes.</p