Phenome-Wide Association Study of Latent Autoimmune Diabetes from a Southern Mexican Population Implicates rs7305229 with Plasmatic Anti-Glutamic Acid Decarboxylase Autoantibody (GADA) Levels

Abstract

Latent autoimmune diabetes in adults (LADA) is characterized by the presence of glutamate decarboxylase autoantibodies (GADA). LADA has intermediate features between type 1 diabetes and type 2 diabetes. In addition, genetic risk factors for both types of diabetes are present in LADA. Nonetheless, evidence about the genetics of LADA in non-European populations is scarce. This study aims to perform a genome-wide association study with a phenome-wide association study of LADA in a southeastern Mexican population. We included 59 patients diagnosed with LADA from a previous study and 3121 individuals without diabetes from the MxGDAR/ENCODAT database. We utilized the GENESIS package in R to perform the genome-wide association study (GWAS) of LADA and PLINK for the phenome-wide association study (PheWAS) of LADA features. Nine polymorphisms reach the nominal association level (1 × 10^-5) in the GWAS. The PheWAS showed that rs7305229 is genome-wide and associated with serum GADA levels in our sample (p = 1.84 × 10^-8). rs7305229 is located downstream of the FAIM2 gene; previous reports associate FAIM2 variants with childhood obesity, body mass index, body adiposity measures, lymphocyte CD8+ activity, and anti-thyroid peroxidase antibodies. Our findings reveal that rs7305229 affects the GADA levels in patients with LADA from southeastern Mexico. More studies are needed to determine if this risk genotype exists in other populations with LADA.

Keywords: Mexico; fas apoptotic inhibitory molecule 2; genome-wide association study; latent autoimmune diabetes of adults.

Figure 1

Manhattan plot of the genome-wide association of GADA in patients with LADA. The gray line marks the threshold for nominal significance. Nominal significance was defined as 5 (−log₁₀(1 × 10⁻⁵)). The red line marks the threshold for genome-wide significance and was defined as 7.3 (−log₁₀(5 × 10⁻⁸)).

Figure 2

Fine mapping of the locus of rs7305229. The superior blue circle marks rs7305229, which had the highest posterior inclusion probability (PIP) of being the causal variant of the GADA levels phenotype (94.8%).