Although approximately 50 percent of the risk of autism spectrum disorder (ASD) is genetic¹, genetics alone is insufficient for diagnosis and imparts little clinical utility for non-syndromic forms of ASD. Given the clinical and etiological heterogeneity of the condition, attention has turned to the search for more homogenous groups of ASD cases. The identification of such groups may further the understanding of ASD etiology and molecular mechanisms, and support the development of novel, targeted management strategies for specific subgroups².

Previously, this search has focused on endophenotypes. Endophenotypes are defined as “intermediate phenotypes” that separate individuals into subgroups based on characteristics, such as neurophysiological, hormonal and behavioral, with a clear genetic connection³. However, these approaches have been hampered by a lack of replication, their complexity, and the limited genetic insights they have imparted to date⁴.

Jessica Ann Lasky-Su and Rachel Kelly argue that the metabolome—the downstream “ome” closest to clinical phenotype that reflects all the preceding “omes” (e.g., genome)—the environment, and crucially, genome environment interactions, represent a compelling intermediate phenotype that can be used to better classify individuals with ASD. In this project, they propose to identify metabolomic endotypes (i.e., subtypes based on their functional/pathobiological mechanisms) by examining plasma metabolomic profiles of 2,517 probands from the Simons Simplex Collection (SSC). They will then leverage comprehensive exposure information, clinical measurements and genome-wide genetic data from the SSC, to (1) determine the clinical and phenotypic characteristics of these metabo-endotypes, (2) explore the metabolomic pathway dysregulation underlying the metabo-endotypes and (3) identify the genetic drivers of the metabo-endotypes. Completion of these aims will both inform on the biological mechanisms of ASD heterogeneity and support the development of precision medicine initiatives for this condition.