This section of the article provides detailed supplemental notes on the methods and findings of a study investigating the role of rare copy-number variants (CNVs) in modulating susceptibility to common diseases. The study utilized microarray-based CNV calling, sample filtering criteria, and various statistical models to analyze the association between CNVs and diseases. Key findings include: 1. **Microarray-based CNV Calling**: CNVs were called using dedicated modalities, with specific procedures to avoid interference between CNV encoding and male chromosome X hemizygosity. 2. **Sample Quality Control**: Samples with high CNV counts or extreme CNV events were excluded to ensure data quality and relevance. 3. **CNV Encoding in PLINK**: CNV matrices were encoded into binary files for analysis, with different models (mirror, U-shape, duplication-only, deletion-only) to mimic various modes of CNV action. 4. **Sample Filtering Criteria**: A series of filters were applied to reduce the sample size from 488,377 to 331,522 individuals for the CNV-GWAS analysis. 5. **Probe and Covariate Selection**: Relevant covariates and probes were pre-selected to fit tailored main CNV GWAS models, reducing computation time and ensuring statistical power. 6. **Post-CNV-GWAS Summary Statistics Processing**: Summary statistics were harmonized and conditional analysis was performed to identify independent CNV-disease associations. 7. **Estonian Biobank Replication**: The study replicated findings in the Estonian Biobank, adjusting for differences in recording practices and excluding certain subcodes. 8. **Subgrouping of CNV Carriers**: CNV carriers were split into subgroups based on visual inspection of breakpoints and segmental duplications in complex CNVRs. 9. **Specific CNV Associations**: - **BRCA1 Deletion**: Associated with increased risk of ovarian and other female cancers, with earlier onset and higher prevalence. - **LDLR Deletion**: Increased risk of ischemic heart disease, with higher prevalence and earlier onset, despite the use of hypolipidemic agents. - **16p12.2 Deletion**: Increased risk of hypertension, cardiac conduction disorders, and pneumonia, with implications for cardiovascular health. - **22q11.2 CNV**: Associated with ischemic heart disease, aneurysm, and headaches, suggesting a spectrum of cardiovascular afflictions. These findings highlight the significant impact of rare CNVs on disease susceptibility and provide insights into the genetic basis of common diseases.This section of the article provides detailed supplemental notes on the methods and findings of a study investigating the role of rare copy-number variants (CNVs) in modulating susceptibility to common diseases. The study utilized microarray-based CNV calling, sample filtering criteria, and various statistical models to analyze the association between CNVs and diseases. Key findings include: 1. **Microarray-based CNV Calling**: CNVs were called using dedicated modalities, with specific procedures to avoid interference between CNV encoding and male chromosome X hemizygosity. 2. **Sample Quality Control**: Samples with high CNV counts or extreme CNV events were excluded to ensure data quality and relevance. 3. **CNV Encoding in PLINK**: CNV matrices were encoded into binary files for analysis, with different models (mirror, U-shape, duplication-only, deletion-only) to mimic various modes of CNV action. 4. **Sample Filtering Criteria**: A series of filters were applied to reduce the sample size from 488,377 to 331,522 individuals for the CNV-GWAS analysis. 5. **Probe and Covariate Selection**: Relevant covariates and probes were pre-selected to fit tailored main CNV GWAS models, reducing computation time and ensuring statistical power. 6. **Post-CNV-GWAS Summary Statistics Processing**: Summary statistics were harmonized and conditional analysis was performed to identify independent CNV-disease associations. 7. **Estonian Biobank Replication**: The study replicated findings in the Estonian Biobank, adjusting for differences in recording practices and excluding certain subcodes. 8. **Subgrouping of CNV Carriers**: CNV carriers were split into subgroups based on visual inspection of breakpoints and segmental duplications in complex CNVRs. 9. **Specific CNV Associations**: - **BRCA1 Deletion**: Associated with increased risk of ovarian and other female cancers, with earlier onset and higher prevalence. - **LDLR Deletion**: Increased risk of ischemic heart disease, with higher prevalence and earlier onset, despite the use of hypolipidemic agents. - **16p12.2 Deletion**: Increased risk of hypertension, cardiac conduction disorders, and pneumonia, with implications for cardiovascular health. - **22q11.2 CNV**: Associated with ischemic heart disease, aneurysm, and headaches, suggesting a spectrum of cardiovascular afflictions. These findings highlight the significant impact of rare CNVs on disease susceptibility and provide insights into the genetic basis of common diseases.