Mendelian randomization study of birthweight, gestational age, and risk of childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and the incidence is increasing.1 Albeit inconsistently, birthweight and gestational age at birth – particularly high birthweight and preterm birth – have been linked to risk of childhood ALL in observational studies, which has been hypothesized to be in part due to intrauterine exposure to growth factors (high birthweight) and immature immune system and antioxidant defense system (preterm birth).2–4 A potential limitation with traditional observational studies is residual confounding. Because genetic variants are allocated at random at conception, they may be used as instrumental variables to assess the unconfounded effect of an exposure on an outcome (mimicking a randomized experiment), often referred to as “Mendelian randomization” (MR) (Supplementary Figure).5 We aimed to evaluate the potential association between genetically-predicted birthweight and gestational duration, and the risk of childhood ALL by conducting a two-sample MR study.