An improved genetic risk score for type 1 diabetes (T1D), called the T1D GRS2, signiﬁcantly improved identification of persons with T1D from those with type 2 diabetes (T2D) and may be useful in differentiating diabetes subtypes and predicting T1D in newborn screening studies, according to findings published in Diabetes Care.
T1D has a largely heritable component, but published genetic risk scores to date have not fully captured all information on risk for T1D at non-human leukocyte antigen (HLA) loci or at HLA risk loci. Researchers have developed a new T1D genetic risk score that incorporates HLA alleles and their interactions more completely and includes recently discovered non-HLA loci. The current study tested the ability of the T1D GRS2 to discriminate diabetes subtypes and to predict T1D in newborn screening in a cohort of 6481 cases and 9247 control participants from the Type 1 Diabetes Genetics Consortium. Variants associated with T1D both in the HLA region and across the genome were analyzed.
The final T1D GRS2 used a total of 67 single nucleotide polymorphisms (14 DR-DQ, 21 other HLA, and 32 non-HLA single nucleotide polymorphisms) and demonstrated markedly improved discrimination of T1D compared with an older T1D genetic risk score. It was also highly discriminative for all T1D (area under the curve, 0.93; P <.0001 vs older scores) and even more so for early-onset T1D (area under the curve, 0.96). When comparing patients with T1D with those with T2D, T1D GRS2 excluded 87.8% of patients with T2D but included 82.7% of patients with T1D. Simulated newborn screening showed that T1D GRS2 was more than twice as efficient as HLA DR-DQ genotyping alone and also proved to be 50% better than the current genetic scores used in the general population.
“The amount of genetic information incorporated into a T1D [genetic risk score] that can be easily used in the clinic and for research must necessarily represent a balance between effective cost of implementation and maximization of genetic information,” wrote the researchers.
Sharp SA, Rich SS, Wood AR, et al. Development and standardization of an improved type 1 diabetes genetic risk score for use in newborn screening and incident diagnosis. Diabetes Care. 2019;42(2):200-207.