Variants influencing age at diagnosis of HNF1A-MODY

Background: HNF1A-MODY is a monogenic form of diabetes caused by variants in the HNF1A gene. Different HNF1A variants are associated with differences in age of disease onset, but other factors are postulated to influence this trait. Here, we searched for genetic variants influencing age of HNF1A-MODY onset. Methods: Blood samples from 843 HNF1A-MODY patients from Czech Republic, France, Poland, Slovakia, the UK and the US were collected. A validation set consisted of 121 patients from the US. We conducted a genome-wide association study in 843 HNF1A-MODY patients. Samples were genotyped using Illumina Human Core arrays. The core analysis was performed using the GENESIS package in R statistical software. Kinship coefficients were estimated with the KING and PC-Relate algorithms. In the linear mixed model, we accounted for year of birth, sex, and location of the HNF1A causative variant. Results: A suggestive association with age of disease onset was observed for rs2305198 (p = 2.09E−07) and rs7079157 (p = 3.96E−06) in the HK1 gene, rs2637248 in the LRMDA gene (p = 2.44E−05), and intergenic variant rs2825115 (p = 2.04E−05). Variant rs2637248 reached nominal significance (p = 0.019), while rs7079157 (p = 0.058) and rs2825115 (p = 0.068) showed suggestive association with age at diabetes onset in the validation set. Conclusions: rs2637248 in the LRMDA gene is associated with age at diabetes onset in HNF1A-MODY patients.