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

• Published in: Journal of psychiatric research Vol. 59; pp. 108 - 116
• Main Authors: Gabriele, Stefano, Lombardi, Federica, Sacco, Roberto, Napolioni, Valerio, Altieri, Laura, Tirindelli, Maria Cristina, Gregorj, Chiara, Bravaccio, Carmela, Rousseau, Francis, Persico, Antonio M
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.12.2014; Elsevier
• Subjects: Adolescent; Adult; Advanced glycation end-products; Alanine - genetics; Autism; Autism spectrum disorder; Biological and medical sciences; Brain - pathology; Child; Child clinical studies; Child Development Disorders, Pervasive - genetics; Child Development Disorders, Pervasive - pathology; Child, Preschool; Developmental disorders; Family Health; Female; Genetic Association Studies; Genotype; Glycation End Products, Advanced; Glyoxalase; Humans; Infantile autism; Lactoylglutathione Lyase - genetics; Lactoylglutathione Lyase - metabolism; Linkage Disequilibrium; Male; Medical sciences; Methylglyoxal; Middle Aged; Pervasive developmental disorders; Polymorphism, Single Nucleotide - genetics; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Serotonin - blood; Serotonin - urine; Statistics as Topic; Young Adult; Autism; Methylglyoxal; Advanced glycation end-products; Glyoxalase; Autism spectrum disorder; Pervasive developmental disorders; Social environment; Reaction product; Developmental disorder; Vulnerability; Glycation; Pervasive developmental disorder; Family environment; Genetics
• ISSN: 0022-3956; 1879-1379
• DOI: 10.1016/j.jpsychires.2014.07.021

Abstract Glyoxalase I (GLO1) is a homodimeric Zn2+ -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  < 0.05 and P  < 0.001 under additive and dominant/recessive models, respectively). Glyoxalase enzymatic activity was significantly reduced both in leukocytes and in post-mortem temporocortical tissue ( N  = 38 and 13, respectively) of typically developing C332 allele carriers ( P  < 0.05 and <0.01), with no difference in Glo1 protein levels. Conversely, AGE amounts were significantly higher in the same C332 post-mortem brains ( P  = 0.001), with a strong negative correlation between glyoxalase activity and AGE levels ( τ  = −0.588, P  < 0.01). Instead, 19 autistic brains show a dysregulation of the glyoxalase-AGE axis ( τ  = −0.209, P  = 0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls ( P  < 0.05), and loss of 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.