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1 A Supplementary figures a) DMT.BG DMT.EG EMT.MG EMT.G6 DMT/EMT b) EG MG G6 Klepel c) BG EG MG G6 RAN_Dig_ss d) PDtot.BG PDtot.EG PDtot.MG PDAKT.G6 PD Figure S1: Correlation panel of phenotypes of interest per phenotype. a) Word reading fluency: DMT test in time-point BG2 and EG2, EMT test in time-point MG3 and G6; c) Rapid Naming Digits; b) Nonword reading fluency; d) Phoneme deletion tests: PD1, PD2 and PDakt. 1

2 a) rs * timepoint timepoint : EG2 timepoint : MG3 timepoint : G6 Z score Klepel C/C C/A A/A C/C C/A A/A C/C C/A A/A Genotype rs b) 1 Z score Klepel Genotype rs C/C C/A A/A 0 EG2 MG3 G6 Time point Figure S2: Z-standardised performance on nonword reading fluency (Klepel test) per educational time-point and genotypic groups of rs a) Interaction plot of time-point x rs b) Fitted residuals to the mixed linear model including the rs and timepoint x rs as variables; the points and error bars are the mean and standard deviation of the mean per time-point. 2

3 B Longitudinal models B.0.1 NRT and PD AKT : 1 time-point Phenotype = β 0 + β 1 age.c + β 2 (1 fam) + β 3 timepoint + β 4 sex + β 5 cohort + β 6 group Phenotype = β 0 + β 1 age.c + β 2 (1 fam) + β 3 timepoint + β 4 sex + β 5 cohort + β 6 group + β 7 SNP i (S1) (S2) B.0.2 DMT and EMT: 2 time-points 3 Phenotype = β 0 + β 1 age.c + β 2 (1 fam) + β 3 (1 id) + β 4 timepoint + β 5 sex + β 6 cohort + β 7 group Phenotype = β 0 + β 1 age.c + β 2 (1 fam) + β 3 (1 id) + β 4 timepoint + β 5 sex + β 6 cohort + β 7 group + β 8 SNP i Phenotype = β 0 + β 1 age.c + β 2 (1 fam) + β 3 (1 id) + β 4 timepoint + β 5 sex + β 6 cohort + β 7 group + β 8 SNP i + β 9 timepoint SNP i (S3) (S4) (S5) B.0.3 Klepel, RAN Dig and PD tot : >3 time-points Phenotype = β 0 + β 1 age.c + β 2 (1 fam) + β 3 (1 + age.c id) + β 4 timepoint + β 5 sex + β 6 cohort + β 7 group Phenotype = β 0 + β 1 age.c + β 2 (1 fam) + β 3 (1 + age.c id) + β 4 timepoint + β 5 sex + β 6 cohort + β 7 group + β 8 SNP i Phenotype = β 0 + β 1 age.c + β 2 (1 fam) + β 3 (1 + age.c id) + β 4 timepoint + β 5 sex + β 6 cohort + β 7 group + β 8 SNP i + β 9 timepoint SNP i (S6) (S7) (S8)

4 C Supplementary tables C.1 Covariates Covariate Age Sex Cohort Group Levels Continuous Male, female Groningen, Nijmegen, Amsterdam Familial Risk, Non-familial risk Table S1: List of covariates that have been regressed out from the raw scores per time-point, and that have been included into the linear regression models. C.2 Mixed effect models, null models Time- Fixed Random Phenotype Measure points terms terms 1 age.c sex cohort group family Nonword Repetition NWR Phoneme Deletion PD AKT 2 age.c sex cohort group family subject Word Reading Fluency DMT Word Reading Fluency >3 age.c sex cohort group family age.c subject Nonword Reading Fluency Klepel Rapid Naming of Digits Phoneme Deletion Table S2: Null models for each measurement, specifying the fixed effect and random terms for each trait, depending on the number of available measures per subject. EMT RAN dig PD tot 4

5 C.3 Likelihood ratio tests Formula Df AIC BIC loglik deviance χ 2 χ 2 df Pr(χ 2 ) H 0 Z EMT age.c + (1 fam) + (1 id) + timep + sex + cohort + group H 1 Z EMT age.c + (1 fam) + (1 id) + timep + sex + cohort + group + rs H 0 Z Klepel age.c + (1 fam) + (1 + age.c id) + timep + sex + cohort + group + rs H 1 Z Klepel age.c + (1 fam) + (1 + age.c id) + timep + sex + cohort + group + rs timep*rs H 0 Z RAN dig age.c + (1 fam) + (1 + age.c id) + timep + sex + cohort + group H 1 Z RAN dig age.c + (1 fam) + (1 + age.c id) + timep + sex + cohort + group + rs H 0 Z RAN dig age.c + (1 fam) + (1 + age.c id) + timep + sex + cohort + group H 1 Z RAN dig age.c + (1 fam) + (1 + age.c id) + timep + sex + cohort + group + rs H 0 Z NWR age.c +(1 fam) + sex + cohort + group H 1 Z NWR age.c +(1 fam) + sex + cohort + group + rs Table S3: Likelihood ratio test (LRT) between nested mixed models for the SNPs and timepoint*snp terms that are nominally significant. For each LRT, the χ 2 statistic and associated P value is shown 5

6 C.4 Haplotype analyses Time-points BG2 EG2 MG3 G6 Haplotype N β R 2 P N β R 2 P N β R 2 P N β R 2 P rs rs e e rs rs e e e e rs rs e Table S4: Haplotype analyses of rs rs for Rapid Naming Digits per time-point. C.5 Conditional analyses 6 BG2 EG2 MG3 G6 SNP test SNP cov N β P N β P N β P N β P rs rs rs rs Table S5: Conditional association of RAN digits with rs and rs from Plink.

7 C.6 LME model estimates Null model estimates, per phenotype (Intercept) age years.c timepointeg sex cohort cohort group Table S6: Estimates for the null model of DMT. (Intercept) age years.c timepointg sex cohort cohort group Table S7: Estimates for the null model of EMT. (Intercept) age years.c timepointmg timepointg sex cohort cohort group Table S8: Estimates for the null model of Klepel. 7

8 (Intercept) age years.c sex cohort cohort group Table S9: Estimates for the null model of NWR. (Intercept) age years.c timepointeg timepointmg sex cohort cohort group Table S10: Estimates for the null model of PD tot. (Intercept) age years.c timepointeg timepointmg timepointg sex cohort cohort group Table S11: Estimates for the null model of RAN dig 8

9 Full model estimates (Intercept) age years.c timepointg sex cohort cohort group rs Table S12: Estimates for the full model of EMT rs (Intercept) age years.c timepointmg timepointg sex cohort cohort group rs timepointmg3:rs timepointg6:rs Table S13: Estimates for the full model of Klepel timepoint*rs interaction. 9

10 (Intercept) age years.c sex cohort cohort group rs Table S14: Estimates for the full model of NWR rs (Intercept) age years.c timepointeg timepointmg timepointg sex cohort cohort group rs Table S15: Estimates for the full model of RAN dig rs (Intercept) age years.c timepointeg timepointmg timepointg sex cohort cohort group rs Table S16: Estimates for the full model of RAN dig rs

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