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Additional file 1: Supplementary Figure 1. Forest plots for the 5 most significant CpGs in female samples meta-analysis of ADNI and AIBL blood sample datasets. Shown are odds ratios and confidence intervals that describe changes in odds of AD (on the multiplicative scale) associated with a one percent increase in DNA methylation beta values (i.e., increase in beta values by 0.01) after adjusting for covariate variables age at visit, batches and proportions of different blood cell types in each sample. Supplementary Figure 2. Forest plots for the 4 significant CpGs with P < 10-5 in male samples meta-analysis of ADNI and AIBL blood sample datasets. Shown are odds ratios and confidence intervals that describe changes in odds of AD (on the multiplicative scale) associated with a one percent increase in DNA methylation beta values (i.e., increase in beta values by 0.01) after adjusting for covariate variables age at visit, batches, and proportions of different blood cell types in each sample. Supplementary Figure 3. Overlap between DMRs and CpGs in males and females. There was no overlap between significant sex-specific DMRs and significant sex-specific individual CpGs in either (A) males or (B) females. Supplementary Figure 4. Comparison of results for DNA methylation differences in female sample meta-analysis vs. male sample meta- analysis. (A) overlap of AD-associated CpGs (B) overlap of AD-associated DMRs and (C) there was only modest correlation between effect estimates for CpG to AD associations in female meta-analysis vs. those from male meta-analysis. Supplementary Figure 5. Performance of different sex-specific logistic regression models for predicting AD diagnosis in out-of-sample validation. The training and testing datasets included samples from the AIBL and AddNeuroMed datasets, respectively. MRS was computed as the sum of methylation beta values for significant CpGs weighted by their estimated effect sizes from the sex-specific meta-analysis of AIBL and ADNI datasets. In males, significant CpGs for the MRS included 2 CpGs with P < 10-5 identified in the interaction analysis that are also available in the AddNeuroMed dataset; in females, significant CpGs for MRS included 9 CpGs with P < 10-5 identified in AD vs. CN comparison that are also available in AddNeuroMed dataset. Abbreviations: AUC = Area Under ROC curve, AD = Alzheimer's disease, CN = cognitive normal. Supplementary Figure 6. The changes in AD-associated B cell type proportions in females were more pronounced than in males in all three datasets (ADNI, AIBL, AddNeuroMed). Supplementary Figure 7. Comparison of years of education (PTEDUCAT) in cognitive normal (CN) and AD subjects from ADNI dataset. There was not significant association between AD status and years of education in females (P = 0.23) or males (P = 0.12), using Wilcoxon rank-sum test.

Additional file 1: Supplementary Figures. Figure S1. Quantile-quantile (QQ) plots of observed and expected distributions of P-values in Gasparoni, London, Mount Sinai, and ROSMAP cohorts. Figure S2. Comparison of methylation-Braak stage associations in female samples and male samples. Figure S3. Enrichment of FDR-significant CpGs and CpGs located within FDR-significant DMRs with positive and negative effect estimates in various genomic features and chromatin states. Figure S4. Gene Set Enrichment of the TYROBP causal network with sex-specific Braak-associated DNA methylation differences. Figure S5. Forest plots for several top CpGs identified in sex-stratified analysis and sex-by-Braak stage interaction analysis.

PurposeDetermination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND).MethodsFifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex.ResultsSubjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners.ConclusionsA consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.