Additive Evidence of Rare and Common Variant Burden Across the Spectrum of Intellectual Disability Severity

Academic Background

Intellectual Disability (ID) is a common condition with a range of severity from mild to profound. Mild ID is often viewed as the lower end of the intelligence distribution, while severe ID is typically considered a monogenic disorder caused by rare, deleterious, high-penetrance variants. This study aims to explore the genetic factors affecting mild and severe intellectual disability and evaluate the role of rare and common variants in a Northern Finnish ID population.

Paper Source

This paper was written by Lea Urpa et al., with authors from multiple research institutions including the University of Helsinki, Stanley Center for Psychiatric Research, Massachusetts General Hospital, and the University of Oulu. The paper was published in the European Journal of Human Genetics in 2024.

Research Process

The study analyzed data from the Northern Finnish Intellectual Disability (NFID) cohort (total of 1096 patients), which is enriched for mild ID cases and rare, deleterious variants due to the population bottleneck effect in Finland. The research employed multi-step quality control, exome sequencing, and multivariate statistical regression methods to analyze the burden of rare and common variants and explore their impact on intellectual disability.

First, the data was processed using stringent sample and genotype quality control procedures, followed by annotation of genetic variants. The study identified potentially pathogenic variants in known ID-related genes and used logistic regression models to evaluate the burden of rare deleterious variants in monoallelic ID genes. Additionally, through the construction of multi-model inference methods, the study compared the explanatory power of rare and common variants for ID status and assessed the additivity of these two types of variants across the entire spectrum of ID severity.

Research Results

The study found that despite the enrichment of rare deleterious variants in the Finnish population, only a small proportion of ID cases were caused by Finland-specific recessive variants (0.5%). In contrast, dominant variants accounted for a larger proportion of the rare deleterious variant burden, with significant burden in both mild and severe ID cases. Furthermore, there was no significant difference in common variant burden between mild and severe ID. When combining common and rare variants in the same model for analysis, it was found that these two types of variants had additive effects in both mild and severe ID.

Conclusions and Significance

This study demonstrates that rare and common variant burdens have additive effects across the entire spectrum of intellectual disability severity. This finding suggests that rare and common variants may jointly shape the genetic risk spectrum of intellectual disability. The results have important implications for understanding the genetic etiology of intellectual disability, especially in terms of diagnostic and intervention strategy development.

Research Highlights

1. First evidence of additive effects of rare and common variant burdens in the Northern Finnish intellectual disability cohort.
2. Suggests that exome sequencing analysis for potential rare variants should also be considered in the clinical diagnosis of mild ID patients.
3. Provides a new perspective on the current understanding of the roles of rare and common variants in ID, laying the foundation for subsequent research.