Background Numerous studies have identified the potential risk factors and biomarkers for autism spectrum disorder (ASD). We aim to study the strength and validity of the suggested environmental risk factors or biomarkers of ASD. Methods We conducted an umbrella review and systematically appraised the relevant meta-analyses of observational studies (PROSPERO registration: CRD42018091704). We searched PubMed, Embase, and Cochrane Database of Systematic Reviews from inception to 10/17/2018 and screened the reference list of relevant articles. We obtained the summary effect, 95% confidence interval (CI), heterogeneity, and 95% prediction intervals. We examined small study effects and excess significance. We performed analyses under credibility ceilings. Findings A total of 46 eligible articles yielded data on 67 environmental risk factors (cases=544212, population=81708787) and 52 biomarkers (cases=15614, controls=15417). Evidence of association was convincing for greater maternal age (RR=1•31, 95% CI=1•18 to 1•45), maternal chronic hypertension (OR=1•48, 95% CI=1•29 to 1•70), maternal gestational hypertension (OR=1•37, 95% CI=1•21 to 1•54), maternal overweight (RR=1•28, 95% CI=1•19 to 1•36), preeclampsia (RR=1•32, 95% CI=1•20 to 1•45), pre-pregnancy maternal antidepressant exposure (RR=1•48, 95% CI=1•29 to 1•71), and selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy (OR=1•84, 95% CI=1•60 to 2•11). Only two associations, maternal overweight and SSRI during pregnancy, retained high level of evidence under subset sensitivity analyses. Evidence from biomarkers was limited. Interpretation Convincing evidence suggests that maternal factors such as age and features of metabolic syndrome are associated with risk of ASD. SSRI use during pregnancy was also convincingly associated with risk of ASD when exposed and non-exposed groups were compared. However, there is a possibility that the association is affected by other confounding factors, considering that pre-pregnancy maternal antidepressant exposure was also convincingly associated with higher risk of ASD. Findings from prior studies suggest that one possible confounding factor is underlying maternal psychiatric disorders.

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Manuscript word count: 4455 words 4 5 Funding 1 None. 2 3

This study aimed to verify noteworthy findings between genetic risk factors and autism spectrum disorder (ASD) by employing the false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP). PubMed and the Genome-Wide Association Studies (GWAS) catalog were searched from inception to 1 August, 2019. We included meta-analyses on genetic factors of ASD of any study design. Overall, twenty-seven meta-analyses articles from literature searches, and four manually added articles from the GWAS catalog were re-analyzed. This showed that five of 31 comparisons for meta-analyses of observational studies, 40 out of 203 comparisons for the GWAS meta-analyses, and 18 out of 20 comparisons for the GWAS catalog, respectively, had noteworthy estimations under both Bayesian approaches. In this study, we found noteworthy genetic comparisons highly related to an increased risk of ASD. Multiple genetic comparisons were shown to be associated with ASD risk; however, genuine associations should be carefully verified and understood.