Autism Risk and Maternal Cardiometabolic Health (ARCH) study

Autism spectrum disorder (ASD) now affects 1 in 59 children in the US and there is no cure. Both genetic and environmental factors contribute substantially to ASD risk, but integration of these factors in ASD etiologic studies – critical steps towards primary prevention – are rare. Cardiometabolic conditions (CMCs: obesity, hypertension, or diabetes prior to pregnancy and hypertensive disorders in pregnancy/pre-eclampsia or gestational diabetes with onset in pregnancy) are prevalent in pregnant women and commonly co-occur; impose serious complications on the pregnancy and the developing fetus; and have shown to effect neurodevelopment, including intellectual disability (ID) and attention deficit hyperactivity disorder (ADHD). The literature and our preliminary data strongly suggest CMCs are associated with ASD risk but critical risk patterns underlying the association (CMC combination, severity, and timing; ASD outcome by ID or ADHD comorbidity or by sex) have been inadequately investigated and could enhance risk detection. Further, no study has investigated whether maternal CMCs affect ASD risk by shared genetics of the mother and her offspring or through independent mechanisms. The goal of the Autism Risk and maternal Cardiometabolic Health (ARCH) Study is to determine the role of maternal CMCs and related familial and genetic factors in ASD etiology via three specific aims (1): Rigorously evaluate maternal CMCs and ASD associations, by combination, timing of onset and severity; (2) Elucidate maternal CMC-ASD risk patterns by ASD comorbid subgroups and child sex; (3) Quantify CMC impact on ASD risk through shared genetic factors; combined offspring ASD genetics and maternal CMC effects; and independent CMC effects. We use a robust, well powered sample of 1.5 million live births (1998-2007) from Denmark and Sweden and linked 3- generation family pedigrees, rigorously harmonized and reproducible exposure (CMC diagnoses, prescriptions), outcome (ASD (25,000 cases), comorbid ID, ADHD diagnoses through 2016; ASD by child sex) and covariate data; and genotype data from the Danish nationwide iPSYCH study for 30,000 ASD cases and controls. Our innovations include the first, rigorous, multi-faceted investigation of CMCs as a class of prevalent, potentially modifiable risks for ASD; critical synthesis of familial and genetic CMC contributions to ASD risk; unique, large-scale comprehensive analysis of multiple exposures and multivariate outcomes to create a holistic picture of maternal CMCs as risk factors for ASD, as well as CMC-ASD genetic interrelationships using innovative genetic modeling approaches of both pedigree and genomic data. Our integrated approach, rigorous methods and unprecedented study power in the hands of our expert team will pave the way to discovery of potentially modifiable risk factors, high-risk subgroups, critical risk pathways, and future ASD prevention strategies.