Genetics of circulating proteins in newborn babies at high risk of type 1 diabetes

Abstract

Type 1 diabetes is a chronic, autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas. Early detection can facilitate timely intervention, potentially delaying or preventing disease onset. Circulating proteins reflect dysregulated biological processes and offer insights into early disease mechanisms. Here, we construct a genome-wide pQTL map of 1985 proteins in 695 newborn babies (median age 2 days) at increased genetic risk of developing Type 1 diabetes. We identify 535 pQTLs (352 cis-pQTLs, 183 trans-pQTLs), 62 of which characteristic of newborns. We show colocalization of pQTLs for CTRB1, APOBR, IL7R, CPA1, and PNLIPRP1 with Type 1 diabetes GWAS signals, and Mendelian randomization causally implicates each of these five proteins in the aetiology of Type 1 diabetes. Our study illustrates the utility of newborn molecular profiles for discovering potential drug targets for childhood diseases of significant concern.

Fig. 1. Genome-wide pQTL signals.

Scatterplot of significant pQTL (p < 5 x 10⁻⁸) variant location against the position of the protein coding gene’s transcription start site. Each dot represents an independent variant. The black point outline identifies pQTLs not previously reported by any of the 46 studies used to define novelty.

Fig. 2. cis-pQTL and T1D colocalizing signals.

LocusZoom plots of colocalized proteins for CTRB1, APOBR and IL7R. The top panels show pQTL p-values, while the bottom panels show T1D GWAS p-values for the same regions for the colocalizing regions. Two independent T1D signals reside in the cis-region near the APOBR transcription start site, with lead variants rs34835 and rs231972. Each T1D signal (in the +/− 1 Mb window) was conditioned against the other using GCTA-COJO. The summary statistics from the conditional analysis were then used for colocalization. Only rs34835, conditioned on rs231972, showed evidence of colocalization and the corresponding PP4 is reported in the figure.