RNASeq for BMI GL study

The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body-mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,674 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup’ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population, and expression of RNA in blood was assessed in a subset of this population. We identified a common variant on chromosome 11, rs4936356, genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p=3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup’ik cohort (-0.09 SD, p=0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p=0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.103 SD (0.02), p=4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; fat percent, -1.39 (0.27) %; lean mass, -0.84 (0.19) kg; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p=0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p=0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p=0.0015). Expression analyses of RNA did not reveal any genes regulated by rs4936356 in leukocytes. In conclusion, we identified a novel variant possibly associated with lower BMI, leaner body type, lower insulin resistance, and a favorable lipid profile. The causal transcript in the locus could potentially be a therapeutic target for improving metabolic health.EGA study EGAS00001004127