3 years ago

Effect of sequence variants on variance in glucose levels predicts type 2 diabetes risk and accounts for heritability

Effect of sequence variants on variance in glucose levels predicts type 2 diabetes risk and accounts for heritability
Sirous Zeinali, Hilma Holm, Fereidoun Azizi, Gudmar Thorleifsson, Kari Stefansson, Unnur Thorsteinsdottir, Erna V Ivarsdottir, Isleifur Olafsson, Arni V Thorsson, Gunnar Sigurdsson, Gudmundur Eyjolfsson, Ragnar Bjarnason, Rafn Benediktsson, Patrick Sulem, Snaevar Sigurdsson, Astradur B Hreidarsson, Maryam S Daneshpour, Valgerdur Steinthorsdottir, Olof Sigurdardottir, Daniel F Gudbjartsson

Sequence variants that affect mean fasting glucose levels do not necessarily affect risk for type 2 diabetes (T2D). We assessed the effects of 36 reported glucose-associated sequence variants1 on between- and within-subject variance in fasting glucose levels in 69,142 Icelanders. The variant in TCF7L2 that increases fasting glucose levels increases between-subject variance (5.7% per allele, P = 4.2 × 10−10), whereas variants in GCK and G6PC2 that increase fasting glucose levels decrease between-subject variance (7.5% per allele, P = 4.9 × 10−11 and 7.3% per allele, P = 7.5 × 10−18, respectively). Variants that increase mean and between-subject variance in fasting glucose levels tend to increase T2D risk, whereas those that increase the mean but reduce variance do not (r2 = 0.61). The variants that increase between-subject variance increase fasting glucose heritability estimates. Intuitively, our results show that increasing the mean and variance of glucose levels is more likely to cause pathologically high glucose levels than increase in the mean offset by a decrease in variance.

Publisher URL: http://dx.doi.org/10.1038/ng.3928

DOI: 10.1038/ng.3928

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