BackgroundAlthough polygenic scores (PGS) for autism have been related to various psychiatric and medical conditions, most studies to date have been conducted in research ascertained populations. We aimed to identify the psychiatric and physical conditions associated with autism PGS in a health care setting.MethodsWe computed PGS for 12,383 unrelated participants of African genetic ancestry (AF) and 65,363 unrelated participants of European genetic ancestry (EU) from Vanderbilt’s de-identified biobank. Next, we performed phenome wide association studies of the autism PGS within these two genetic ancestries.ResultsSeven associations surpassed the Bonferroni adjusted threshold for statistical significance (p= 0.05/1374 = 3.6 × 10−5) in the EU participants, including mood disorders (OR (95%CI) = 1.08(1.05 to 1.10),p= 1.0 × 10−10), autism (OR (95%CI) = 1.34(1.24 to 1.43),p= 1.2 × 10–9), and breast cancer (OR (95%CI) = 1.09(1.05 to 1.14), 2.6 × 10−5). There was no statistical evidence for PGS-phenotype associations in the AF participants. Conditioning on the diagnosis of autism or on median body mass index (BMI) did not impact the strength of the reported associations. Although we observed some sex differences in the pattern of associations, there was no significant interaction between sex and autism PGS. Finally, the associations between autism PGS and autism diagnosis were stronger in childhood and adolescence, while the associations with mood disorders and breast cancer were stronger in adulthood.DiscussionOur findings indicate that autism PGS is not only related to autism diagnosis but may also be related to adult-onset conditions, including mood disorders and some cancers.ConclusionsOur study raises the hypothesis that genes associated with autism may also increase the risk for cancers later in life. Future studies are necessary to replicate and extend our findings.Supplementary InformationThe online version contains supplementary material available at 10.1186/s11689-023-09485-x.