Comparative Analysis of Rare Variant Evaluation in Multiple Distinct Phenotypes

In the realm of clinical genetics, the evaluation and interpretation of rare genetic variants in relation to multiple distinct phenotypes is a complex and evolving field. Recent advancements in genomics have empowered researchers to conduct thorough genome-wide analyses, enhancing our understanding of how rare variants influence a multitude of phenotypes. Two distinct but complementary approaches, namely top-down variant filtering and the combination of variants in the same attributes, have emerged as primary methodologies in this domain. In this blog post, we will delve into these approaches, drawing on insights from two cutting-edge studies published in prominent scientific journals.

1. Top-Down Variant Filtering Approach

A recent study published in Nature Communications highlighted the utilization of a top-down variant filtering approach in the context of rare variant analysis across thousands of phenotypes. The study involved genome-wide analysis of rare variants in over 70,000 exomes from two distinct cohorts. This approach primarily focused on the gene-based collapsing analysis, where rare variants were aggregated within genes to identify associations with various phenotypes. The researchers explored two gene-based collapsing models: all non-benign coding and only loss of function (LoF) variants. This methodology was instrumental in identifying 47 significant associations from the meta-analysis of the two cohorts. Furthermore, the approach included a rigorous mechanism to reduce test statistic inflation, especially for binary traits, by setting stringent criteria for the inclusion of genes in the linear mixed model (LMM) analysis. The high rate of replication of signals identified in the discovery cohort bolstered confidence in the associations identified for phenotypes that were only measured in one cohort and not the other​​.

2. Combination of Variants in the Same Attributes Approach

Another innovative approach, outlined in the European Journal of Human Genetics, involved the combination of variants in the same attributes to prioritize variant analysis for unsolved rare diseases. This study leveraged ontologies like the Human Phenotype Ontology (HPO), the Orphanet Rare Disease Ontology (ORDO), and HOOM (HPO-ORDO Ontological Module) to ensure data standardization and facilitate the analysis of phenotypic similarities. The study utilized a sophisticated algorithm, runSolveRD.jar, capable of computing similarity measures and generating clusters around each case or ORPHAcode to maximize one-to-all phenotypic similarity explorations. This approach was particularly beneficial in identifying candidate pathogenic variants, which were then analyzed using genomic data filtered by specific criteria like rarity, protein impact, and clinical significance according to ACMG guidelines. The final evaluation of the variants was conducted by referring clinicians during a multidisciplinary meeting, ensuring a comprehensive and clinically relevant interpretation of the results​​.

Comparative Analysis

Both the top-down variant filtering approach and the combination of variants in the same attributes approach offer unique advantages and cater to specific aspects of rare variant analysis. The top-down approach is highly effective in identifying significant associations between genes and phenotypes by collapsing rare variants within genes. This method is particularly advantageous in studies involving large cohorts, as it allows for the aggregation of rare variants to achieve statistical significance. On the other hand, the combination of variants in the same attributes approach excels in cases where phenotypic similarity and detailed variant prioritization are crucial. By leveraging ontologies and advanced algorithms, this method provides a nuanced analysis that is invaluable for diagnosing and understanding unsolved rare diseases.

In conclusion, the evaluation of rare variants in the context of multiple distinct phenotypes is a multifaceted field that benefits greatly from the integration of diverse analytical approaches. Whether through top-down variant filtering or the combination of variants in the same attributes, researchers are equipped with powerful tools to unravel the complex genetic underpinnings of rare diseases and advance our understanding of genotype-phenotype relationships. As the field continues to evolve, the synergy between these methodologies will undoubtedly pave the way for groundbreaking discoveries and innovations in clinical genetics.

Reference:

Cirulli, E. T., White, S., Read, R. W., Elhanan, G., Metcalf, W. J., Tanudjaja, F., ... & Washington, N. L. (2020). Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts. Nature communications, 11(1), 542.
Lagorce, D., Lebreton, E., Matalonga, L., Hongnat, O., Chahdil, M., Piscia, D., ... & Rath, A. (2023). Phenotypic similarity-based approach for variant prioritization for unsolved rare disease: a preliminary methodological report. European Journal of Human Genetics, 1-8.