The minor allele of rs373863828, a missense variant in CREBRF, has been associated with lower fasting glucose (FG) in Samoans. This variant is common in Polynesians (reported minor allele frequency [MAF] range: 0.096–0.259) but very rare in non-Polynesian populations (MAF<0.001). Other variation in the region may affect FG in other populations. We explore here whether rare variation in the CREBRF region is associated with FG in non-Polynesians in NHLBI’s TOPMed Program. We used whole-genome sequencing data from 11 TOPMed studies with reported FG and excluded individuals with type 2 diabetes. We divided the sample into four groups based on self-reported ancestry (African, n=6,551; Asian, n=2,309; European, n=18,013; and Hispanic, n=1,054). We used SKAT-O to test rare variation for association with FG, adjusting for age, sex, BMI, and ancestry. We selected rare SNPs in the CREBRF region (gene boundaries  50 base pairs) with a TOPMed-wide minor allele count  10 and excluded intergenic variants. Within each ancestry group, we excluded SNPs with a MAF > 0.05. First, we used a sliding window approach covering the region with 41 windows (4 kilobase (kb) with 2 kb overlap) with 28 to 348 variants per window and a median of 106. We set a conservative significance threshold of p<6×10−4 based on the number of non-overlapping windows and ancestry groups (0.05/(21×4)). We found a significant association between a European window of 263 variants and FG (p=2.9×10−4). The window comprises the last 3.3 kb of intron 8 and the first 0.7 kb of exon 9, including the stop codon. However, we did not see significant evidence of association in other ancestries, and the location of the peak association was not consistent between ancestry groups (African: p=0.014, 185 variants; Asian: p=0.023, 76 variants; Hispanic: p=1.7×10−3, 62 variants).

Second, we completed a gene-based analysis of the same CREBRF region. Our significance threshold was p<0.013 given the number of ancestry groups tested (0.05/4). In this analysis, we did not see significant evidence of association of CREBRF with FG in any ancestry (African: p=0.097, 3,319 variants; Asian: p=0.261, 1,671 variants; European: p=0.027, 4,643 variants; Hispanic: p=0.018, 1,336 variants). These results suggest that rare variation in the CREBRF region could be affecting the variance of FG in Europeans. It is possible that with more power association between rare variation and FG could be detected in other ancestries.