African genetic ancestry populationPheWAS

No associations passed the Bonferroni significance threshold (p = 0.05/648 tests = 7.7 × 10−5). Due to the lack of significant associations, no further analyses were performed (Table 2, Fig. 1, Supplementary Table S1).

Table 2 Summary of PheWAS resultsFig. 1

Manhattan plot of pheWAS results for the autism PGS in individuals of African genetic ancestries. The y-axis shows the -log10 transformed p values multiplied by the direction of effect. The dots represent the phecodes which are grouped along the X axis by phecode category. Size of the dot corresponds to the effect size. The colors of the dots indicate the phecode categories, which are explained in the figure. The dotted red line signifies the Bonferroni-corrected threshold for statistical significance

European genetic ancestry populationPheWAS

Seven associations surpassed the Bonferroni significance threshold (p = 0.05/1374 = 3.6 × 10−5), 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), breast cancer (OR (95%CI) = 1.09(1.05 to 1.14), 2.6 × 10−5), depression (OR (95%CI) = 1.07(1.04 to 1.09), p = 3.1 × 10−8, pervasive developmental disorders (OR (95%CI) = 1.15(1.10 to 1.20), p = 2.7 × 10−7), malignant neoplasm of female breast (OR (95%CI) = 1.10(1.05 to 1.14), p = 2.1 × 10−5), and breast cancer [female] (OR (95%CI) = 1.09(1.05 to 1.14), p = 2.6 × 10−5) (Table 2, Fig. 2, Supplementary Table S2). The association with autism yielded the largest effect size, followed by pervasive developmental disorders (OR (95%CI) = 1.15 (1.10 to 1.20), 2.7 × 10−7).

Fig. 2

Manhattan plot of autism PGS in individuals of European genetic ancestries. The y-axis shows the -log10 transformed p values multiplied by the direction of effect. The dots represent the phecodes which are grouped along the X axis by phecode category. Size of the dot corresponds to the effect size. The colors of the dots indicate the phecode categories, which are explained in the figure. The dotted red line signifies the Bonferroni-corrected threshold for statistical significance

Conditioning on BMI

When BMI was added as a covariate in the PheWAS, all previously significant associations remained largely unchanged (Supplementary Table S3).

Conditioning on autism diagnosis

When autism was added as a covariate in the PheWAS, all previously significant associations remained largely unchanged, apart from the associations with autism and pervasive developmental disorders which, as expected, were no longer significant (Supplementary Table 4).

Sex-stratified PheWAS

Autism PGS was associated with autism in males (OR (95%CI) = 1.28(1.17 to 1.38), p = 6.9 × 10−6) (Table 3, Supplementary Table 5, Fig. 3) and females (OR (95%CI) = 1.56(1.36 to 1.75), p = 9,4 × 10−6) (Table 3, Supplementary Table 6, Fig. 4). In females, autism PGS was also associated with mood disorders (OR (95%CI) = 1.09 (1.06 to 1.12), p = 9.3 × 10−10), depression (OR (95%CI) = 1.09 (1.06 to 1.12), p = 3.8 × 10−8), malignant neoplasm of female breast (OR (95%CI) = 1.10 (1.05 to 1.14), p = 2.23 × 10−5), and breast cancer (OR (95%CI) = 1.09 (1.05 to 1.14), p = 2.7 × 10−5). The sex-interaction test indicated that there was no statistical evidence of differences between the sexes once the baseline prevalence of the condition in the sample was taken into account (Table 3, Supplementary Table S7). However, we do observe that the ORs for autism PGS are notably higher in females with an autism diagnosis (OR = 1.56) compared to males with an autism diagnosis (OR = 1.28) suggesting that autistic females may have to reach a higher threshold of genetic likelihood before they come to clinical attention.

Table 3 Sex-stratified results in the European genetic ancestry populationFig. 3

Manhattan plot of autism PGS in males of European genetic ancestries. The y-axis shows the -log10 transformed p-values multiplied by the direction of effect. The dots represent the phecodes which are grouped along the X axis by phecode category. Size of the dot corresponds to the effect size. The colors of the dots indicate the phecode categories, which are explained in the figure. The dotted red line signifies the Bonferroni-corrected threshold for statistical significance

Fig. 4

Manhattan plot of autism PGS in females of European genetic ancestries. The y-axis shows the -log10 transformed p-values multiplied by the direction of effect. The dots represent the phecodes which are grouped along the X-axis by phecode category. Size of the dot corresponds to the effect size. The colors of the dots indicate the phecode categories, which are explained in the figure. The dotted red line signifies the Bonferroni-corrected threshold for statistical significance

Age-stratified PheWASBirth–11-year age group

Autism PGS was associated with autism diagnosis in this age group (OR (95%CI) = 1.28 (1.16 to 1.40), p = 3.0 × 10−5) (Table 4, Supplementary Table 8). No other associations surpassed the Bonferroni significance threshold.

Table 4 PheWAS results by age-group (European genetic ancestry population)12–18-year age group

Similar to the 0 to 11 age group, autism PGS was associated with autism (OR (95%CI) = 1.36 (1.22 to 1.50), p = 1.9 × 10−5) (Table 4, Supplementary Table S9). No other associations surpassed the Bonferroni significance threshold.

19 to 25-year age group

There was no evidence for associations in this age group (Table 4, Supplementary Table S10).

26 to 40-year age group

Autism PGS was associated with mood disorders (OR (95%CI) = 1.22 (1.07 to 1.17, p = 1.1 × 10−5), and depression (OR (95%CI) = 1.13 (1.07 to 1.19), p = 3.4 × 10−5) in this age group (Table 4, Supplementary Table S11).

41 to 60-year age group

Autism PGS was associated with mood disorders (OR (95%CI) = 1.09 (1.06 to 1.13, p = 7.7 × 10−8) and depression (OR (95%CI) = 1.09 (1.05 to 1.12), p = 2.8 × 10−6), while there was a negative association with electrolyte imbalance (OR (95%CI) = 0.93, 0.89 to 0.96), p = 2.8 × 10−5) (Table 4, Supplementary Table S12).

61 to 100-year age group

There was no evidence for associations in this age group (Table 4, Supplementary Table S13).