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Vitamin B12 is an important cofactor in one-carbon metabolism whose dysregulation is associated with various clinical conditions. Indians have a high prevalence of B12 deficiency but little is known about the genetic determinants of circulating B12 concentrations in Indians. We performed a genome-wide association study in 1001 healthy participants in the Pune Maternal Nutrition Study (PMNS), replication studies in 3418 individuals from other Indian cohorts and by meta-analysis identified new variants, rs3760775 ( P  = 1.2 × 10 −23 ) and rs78060698 ( P  = 8.3 × 10 −17 ) in  FUT6  to be associated with circulating B12 concentrations. Although  in-silico  analysis replicated both variants in Europeans, differences in the effect allele frequency, effect size and the linkage disequilibrium structure of credible set variants with the reported variants suggest population-specific characteristics in this region. We replicated previously reported variants rs602662, rs601338 in  FUT2 , rs3760776, rs708686 in  FUT6 , rs34324219 in  TCN1  (all  P  &lt; 5 × 10 −8 ), rs1131603 in  TCN2  ( P  = 3.4 × 10 −5 ), rs12780845 in  CUBN  ( P  = 3.0 × 10 −3 ) and rs2270655 in  MMAA  ( P  = 2.0 × 10 −3 ). Circulating B12 concentrations in the PMNS and Parthenon study showed a significant decline with increasing age ( P  &lt; 0.001), however, the genetic contribution to B12 concentrations remained constant. Luciferase reporter and electrophoretic-mobility shift assay for the  FUT6  variant rs78060698 using HepG2 cell line demonstrated strong allele-specific promoter and enhancer activity and differential binding of HNF4α, a key regulator of expression of various fucosyltransferases. Hence, the rs78060698 variant, through regulation of fucosylation may control intestinal host-microbial interaction which could influence B12 concentrations. Our results suggest that in addition to established genetic variants, population-specific variants are important in determining plasma B12 concentrations.

GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians