Better understanding of the etiologic roles of family history, prenatal environmental factors, and potential biologic mechanisms, such as epigenetic changes, in autism spectrum disorders (ASD) are research priorities identified in the Autism Coordinating Committee 2011 Strategic Plan for Autism Spectrum Disorder Research, but rapid progress is hampered by the challenges of acquiring relevant data in large epidemiologic samples. The goals of the current proposal are to examine: (1) fundamental controversies concerning familial and environmental contributions to risk for ASD;(2) transmission of risk across generations;(3) investigate pregnancy-related environmental factors in ASD, and (4) the potential role of epigenetic changes in those factors. We will build on an existing research network leveraging established population-based epidemiologic resources from seven countries (USA-California, Australia, Denmark, Finland, Israel, Norway, Sweden) that include individual-level perinatal medical, and demographic information and archived biospecimens. Study data will be based on over 4.5 million births (1998-2007), over 20,000 cases of ASD, and family linkages over three generations (grandparents, parents/aunts/uncles, siblings/cousins). Using this unparalleled resource, we propose a novel multigenerational perspective in ASD risk across four integrated aims:
Aim 1 : Model familial recurrence risk and the contributions of shared environmental factors to ASD liability, building on advanced modeling approaches using extended family relations.
Aim 2 : Determine if parental components of ASD risk are transmitted across generations, specifically, advancing parental/grandparental age and parental/grandparental immigration of minority groups.
Aim 3 : Examine ASD risk from prenatal exposure to medications with potential adverse neurodevelopmental effects: a) valproate;b) ?2-adrenergic receptor agonists;c) selective serotonin reuptake inhibitors;or d) antibiotics that impede folate metabolism, i.e., sulfonamides and Trimethoprim.
Aim 4 : Using genomic DNA extracted from archived neonatal blood-spot samples, examine epigenetic changes in children with ASD exposed prenatally to the maternal medications in the previous aim. The resource established by the MINERvA Network will allow more accurate and precise determination of the contributions of familial and environmental factors to the etiology of autism, in particular if medications for maternal chronic and acute conditions prescribed in pregnancy contribute to ASD risk, and whether epigenetic processes underlie a biological abnormality linked to autism. From a public health perspective the study will accelerate the characterization of high risk groups, modifiable risk factors and the elucidation of mechanisms in autism etiology that could ultimately contribute to preventive measures or interventions and treatments.
Using existing population-based epidemiologic resources, our goal is to examine how familial and environmental risks for autism may track through families and across generations, from grandparents, parents and to their children. This approach will set a new bar for epidemiologic investigation and accelerate our understanding of the contribution of the environment to the etiology of autism.
|Viktorin, Alexander; Levine, Stephen Z; Altemus, Margret et al. (2018) Paternal use of antidepressants and offspring outcomes in Sweden: nationwide prospective cohort study. BMJ 361:k2233|
|Yip, Benjamin Hon Kei; Bai, Dan; Mahjani, Behrang et al. (2018) Heritable Variation, With Little or No Maternal Effect, Accounts for Recurrence Risk to Autism Spectrum Disorder in Sweden. Biol Psychiatry 83:589-597|
|Janecka, Magdalena; Kodesh, Arad; Levine, Stephen Z et al. (2018) Association of Autism Spectrum Disorder With Prenatal Exposure to Medication Affecting Neurotransmitter Systems. JAMA Psychiatry 75:1217-1224|
|Hannon, Eilis; Schendel, Diana; Ladd-Acosta, Christine et al. (2018) Elevated polygenic burden for autism is associated with differential DNA methylation at birth. Genome Med 10:19|
|Levine, Stephen Z; Kodesh, Arad; Viktorin, Alexander et al. (2018) Association of Maternal Use of Folic Acid and Multivitamin Supplements in the Periods Before and During Pregnancy With the Risk of Autism Spectrum Disorder in Offspring. JAMA Psychiatry 75:176-184|
|Arora, Manish; Reichenberg, Abraham; Willfors, Charlotte et al. (2017) Fetal and postnatal metal dysregulation in autism. Nat Commun 8:15493|
|Viktorin, Alexander; Uher, Rudolf; Kolevzon, Alexander et al. (2017) Association of Antidepressant Medication Use During Pregnancy With Intellectual Disability in Offspring. JAMA Psychiatry 74:1031-1038|
|Viktorin, A; Uher, R; Reichenberg, A et al. (2017) Autism risk following antidepressant medication during pregnancy. Psychol Med 47:2787-2796|
|Sandin, Sven; Lichtenstein, Paul; Kuja-Halkola, Ralf et al. (2014) The familial risk of autism. JAMA 311:1770-7|