Unraveling the metabolomic architecture of autism in a large Danish population-based cohort

The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental and prenatal factors, the molecular etiology of autism is largely unknown. Metabolomics has emerged as a tool to measure small molecules that reflect genetic, gut microbiome and dietary intake variations. Here, we apply untargeted metabolomics to over 1400 neonatal dried bloods spots, including neonates who later are diagnosed with autism and matching controls. Overall, we detect underlying molecular perturbations that precede autism related to metabolism of amino acids, acylcarnitines and peptides. In particular the cyclic dipeptide cyclo-leucine-proline and the carnitine-related 5-aminovaleric acid betaine (5-AVAB), were associated with an increased probability for autism. Analysis of genetic and dietary data in over 7000 adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy and with variants SLC22A5 , coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. We identify 5-AVAB as a novel and potentially modifiable early biomarker for autism that may influence carnitine homeostasis.