The article discusses the issue of "missing heritability" in complex diseases, where genome-wide association (GWA) studies have explained only a small portion of the genetic variance. Seven leading geneticists offer their insights on where this missing heritability might be found and how it could inform research strategies. Key points include: 1. **Large Variants and Structural Diversity**: Large structural variants (deletions, duplications, inversions) that are individually rare but collectively common in the human population may contribute significantly to missing heritability. These variants affect transcription and are associated with various diseases. 2. **Copy-Number Polymorphisms (CNPs)**: CNPs, which map to regions of copy-number polymorphism, are highly variable among individuals and are enriched in genes related to drug detoxification, immunity, and environmental interaction. They are challenging to study due to their repetitive and multicopy nature but could have a substantial impact on common diseases. 3. **Parent-of-Origin Effects**: Some variants influence disease risk only when inherited from a specific parent, and these effects can be sex-specific. Parent-of-origin effects are underexplored but could account for a significant portion of missing heritability. 4. **Epigenetic and Transgenerational Effects**: Epigenetic effects beyond imprinting, sequence-independent changes that can be transmitted across generations, and transgenerational effects where phenotypic variation in the present generation results from genetic variants in previous generations, are potential sources of missing heritability. 5. **Rare Variants**: While GWA studies have identified common variants, rare variants with larger effect sizes may also contribute to missing heritability. Methods for detecting associations with rare variants are being developed and are crucial for understanding their role in complex traits. 6. **Epistasis and Gene-Environment Interactions**: The complex interactions between genetic variants and environmental factors, such as lifestyle and prenatal conditions, can further complicate the genetic architecture of diseases. These interactions are often not captured by GWA studies and require additional research. 7. **Future Directions**: The authors emphasize the need for more comprehensive assessments of human genetic variation, including large structural variants, CNPs, and epigenetic effects. They also highlight the importance of developing statistical and computational methods to detect and analyze these complex genetic interactions. Overall, the article underscores the complexity of the genetic architecture of complex diseases and the need for a multi-faceted approach to uncovering the missing heritability.The article discusses the issue of "missing heritability" in complex diseases, where genome-wide association (GWA) studies have explained only a small portion of the genetic variance. Seven leading geneticists offer their insights on where this missing heritability might be found and how it could inform research strategies. Key points include: 1. **Large Variants and Structural Diversity**: Large structural variants (deletions, duplications, inversions) that are individually rare but collectively common in the human population may contribute significantly to missing heritability. These variants affect transcription and are associated with various diseases. 2. **Copy-Number Polymorphisms (CNPs)**: CNPs, which map to regions of copy-number polymorphism, are highly variable among individuals and are enriched in genes related to drug detoxification, immunity, and environmental interaction. They are challenging to study due to their repetitive and multicopy nature but could have a substantial impact on common diseases. 3. **Parent-of-Origin Effects**: Some variants influence disease risk only when inherited from a specific parent, and these effects can be sex-specific. Parent-of-origin effects are underexplored but could account for a significant portion of missing heritability. 4. **Epigenetic and Transgenerational Effects**: Epigenetic effects beyond imprinting, sequence-independent changes that can be transmitted across generations, and transgenerational effects where phenotypic variation in the present generation results from genetic variants in previous generations, are potential sources of missing heritability. 5. **Rare Variants**: While GWA studies have identified common variants, rare variants with larger effect sizes may also contribute to missing heritability. Methods for detecting associations with rare variants are being developed and are crucial for understanding their role in complex traits. 6. **Epistasis and Gene-Environment Interactions**: The complex interactions between genetic variants and environmental factors, such as lifestyle and prenatal conditions, can further complicate the genetic architecture of diseases. These interactions are often not captured by GWA studies and require additional research. 7. **Future Directions**: The authors emphasize the need for more comprehensive assessments of human genetic variation, including large structural variants, CNPs, and epigenetic effects. They also highlight the importance of developing statistical and computational methods to detect and analyze these complex genetic interactions. Overall, the article underscores the complexity of the genetic architecture of complex diseases and the need for a multi-faceted approach to uncovering the missing heritability.