The GLO1 C332 (Ala111) allele confers autism vulnerability: Family-based genetic association and functional correlates

Abstract Glyoxalase I (GLO1) is a homodimeric Zn 2+ -dependent isomerase involved in the detoxification of methylglyoxal and in limiting the formation of advanced glycation end-products (AGE). We previously found the rs4746 A332 (Glu111) allele of the GLO1 gene, which encodes for glyoxalase I, associated with “unaffected sibling” status in families with one or more children affected by Autism Spectrum Disorder (ASD). To identify and characterize this protective allele, we sequenced GLO1 exons and exon–intron junctions, detecting two additional SNPs ( rs1049346 , rs1130534 ) in linkage disequilibrium with rs4746 . A family-based association study involving 385 simplex and 20 multiplex Italian families yielded a significant association with autism driven only by the rs4746 C332 (Ala111) allele itself ( P P N  = 38 and 13, respectively) of typically developing C332 allele carriers ( P P  = 0.001), with a strong negative correlation between glyoxalase activity and AGE levels ( τ  = −0.588, P τ  = −0.209, P  = 0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls ( P rs4746 genotype effects. In summary, the GLO1 C332 (Ala111) allele confers autism vulnerability by reducing brain glyoxalase activity and enhancing AGE formation, but years after an autism diagnosis the glyoxalase-AGE axis appears profoundly disrupted, with loss of C332 allelic effects.