introduction
Monogenic developmental disorder (DD) is a disorder caused by variations in a single gene that affect an individual's neurological development and bodily functions. These disorders usually manifest themselves in early childhood and affect a variety of functions, including intelligence, motor ability, and language skills. Rare variants (rare variants), especially those with very low frequencies in the population, have been shown to play a key role in the development of monogenic developmental disorders. These variants include loss-of-function (LoF) and deleterious missense variants, which can directly disrupt genetically encoded proteins, thereby interfering with cellular function and developmental processes. In terms of clinical manifestations, developmental disorders caused by rare genetic variants can range from mild learning disabilities to severe problems with physical and mental development. The variability of these manifestations reflects the heterogeneity of genetic variation in organisms and how they interact with other genetic and environmental factors. In the study, "Genetic modifiers of rare variants in monogenic developmental disorder loci", published April 18 in Nature Genetics, the researchers explored in detail how to study the cumulative effects of rare deleterious variants in 599 dominant developmental disorder (DD) genes using UK Biobank data, as well as EA-PGS ( Educational Attainment Polygenic Score). Studies have noted that individuals carrying 2 to 5 rare deleterious variants exhibit adverse effects of addition in cognitive and socioeconomic traits, and this phenotypic deviation may be explained in part by the enrichment or depletion of rare DD variants. In addition, the study also found that carriers of rare DD variants with a clinical diagnosis of DD showed a significantly lower EA-PGS than carriers without a clinical diagnosis, exhibiting a more severe phenotype. The study utilised UK Biobank's exome sequencing and microarray data and involved approximately 419,000 individuals of genetically defined European ancestry. With these data, the researchers identified individuals who carried rare loss-of-function (pLoF) variants or deleterious missense variants in 599 genes documented in DDG2P (Developmental Disorders Genotype-to-Phenotype Database). These analyses revealed that the increased burden of rare variants was associated with multiple DD-related phenotypes and diagnoses. At the heart of the study is to reveal how rare and common variants work together to affect the expression of an individual's phenotype and potentially determine whether an individual meets the threshold for clinical disease. In addition, these findings may also have important implications for predicting individual disease risk and developing personalized medicine strategies.
Highlights
Cumulative effects of rare variantsThis study found that the accumulation of multiple rare impairment variants in specific Dominant Developmental Disorders (DD) genes had significant superimposed adverse effects on cognitive and socioeconomic characteristics. This was confirmed by analysis of a large data set (UK Biobank), highlighting the important contribution of rare genetic variants to the phenotypic diversity of populations.
The results of the moderating study of educational achievement polygenic score suggest that educational attainment polygenic score (EA-PGS) can partially offset the adverse effects of rare DD gene variants. This suggests that, in addition to rare variants, common variants also play an important role in the formation of individual phenotypes, especially in terms of education and cognitive ability.
The Rare Variant and Phenotype "Deviator" study further explored individuals whose genetic predisposition did not match the actual phenotype (phenotypic "deviators") and found that the carriage of rare DD variants was higher in these individuals. This finding has important implications for clinical prediction, especially in genetic testing and early diagnosis of rare diseases.
Interaction of Rare and Common Genetic VariantsThis study also shows how rare and common genetic variants work together to affect phenotypes in non-clinical populations, revealing the presence of possible etiological variant carriers of monogenic disorders in healthy populations. This underscores the complexity and diversity of genetic backgrounds in disease expression and clinical phenotype.
Strategies
Identification and analysis of rare variantsIn this study, the researchers first used data from the UK Biobank (UKB) to identify variants carrying rare predicted loss-of-function (pLoF) and deleterious variants through exome sequencing and microarray data missense variants). Rare variants are genetic variants that occur with a very low frequency in participants that can lead to loss or alteration of gene function.
The Educational Attainment Polygenic Score (EA-PGS) is used in applied research on polygenic scores to assess the genetic predisposition of individuals. The EA-PGS is calculated based on the cumulative effect of a large number of common genetic variants, each of which may have a small effect on educational achievement, but combined to significantly predict an individual's performance in the field of education.
Assessing phenotypic characteristicsUsing UK Biobank's rich phenotypic data, the research team assessed a variety of socioeconomic characteristics, including cognitive function, years of education, employment status, and more. This phenotypic data allows researchers to explore how rare variants and polygenic scores work together to influence these complex human traits.
Statistical AnalysisBy performing linear regression and logistic regression analyses, the researchers assessed the association between rare variant burden and various phenotypes. These statistical tests helped identify the specific impact of an increase in the number of rare variants on cognitive and socioeconomic outcomes.
The stratified analysis study also performed a stratified analysis in which participants from UK Biobank were divided into different quintiles based on their EA-PGS and the phenotypic association test was repeated. This approach allows researchers to explore in detail differences in phenotypic expression in different genetic contexts.
The gene-phenotype correlation study also explored the genome-wide Association Studies (GWAS) loci for educational achievement and the Developmental Disorders Gene-to-Phenotype Database, DDG2P) to assess whether these genes are spatially close to genes associated with rare diseases, potentially revealing rare and common variants acting through overlapping biological pathways.
Behind the Scenes
Cumulative Effect of Rare Variants Rare variants typically refer to genetic variants that occur at very low frequency in a population and that may cause significant genetic disorders or have a significant impact on phenotype. In this study, rare variants mainly include predicted loss-of-function (pLoF) and deleterious missense variants. The cumulative effect of rare variants refers to the phenomenon in which multiple rare variants in an individual interact to affect the phenotype, especially in the developmental disorders (DD) gene.
The Evidence & Data for Cumulative Effects study used data from the UK Biobank (UKB) and covered genetic and phenotypic information from 419,854 adults. The analysis showed that about 12% of these participants carried at least one rare potentially harmful variant. Furthermore, the study found that individuals with multiple rare variants exhibited more significant adverse effects on multiple cognitive and socioeconomic characteristics. For example, these individuals scored lower on mobile intelligence tests, had shorter years of schooling, had lower employment rates, had lower incomes, and had lower socioeconomic status (as measured by the Townsend Deprivation Index (TDI).
Statistical analysis of the association between rare variants and phenotypes was carried out through linear regression and logistic regression models, and the relationship between the burden of rare variants and specific phenotypes was analyzed in detail. The results showed that with the increase in the number of rare variants (especially more than 2), the performance of carriers of multiple rare variants in mobile intelligence, height, years of education, income, and socioeconomic status decreased significantly compared with individuals who carried only one rare variant or no rare variant. For example, individuals with three or more rare variants were 2.1 times more likely to be diagnosed with a childhood developmental disorder (Child DD) than non-carriers (95% CI, 1.05–4.33; P = 0.03), which was 1.7-fold higher in adult neuropsychiatric conditions (95% CI, 1.01–2.89; P = 0.04）。
Biological Mechanisms of the Cumulative Effect of Rare VariantsThe cumulative effect of rare variants may be achieved through a variety of biological pathways, including intergenic interactions, epigenetic regulation, and interference in protein networks. These complex interactions can lead to alterations in gene expression, affecting cellular function and metabolic pathways, resulting in cumulative phenotypic effects.
The Mitigation Effect of Educational Attainment Polygenic Score (EA-PGS) The Educational Attainment Polygenic Score (EA-PGS) is a score calculated based on the results of large-scale Genome-Wide Association Studies (GWAS) to predict an individual's performance in the field of education. This score assesses an individual's genetic predisposition by adding up the effect sizes of multiple common genetic variants associated with educational achievement. In this study, EA-PGS was used as a tool to explore whether it could mitigate adverse phenotypic effects caused by rare variants.
The mitigation effect of EA-PGSThrough an analysis of the adult population in the UK Biobank, it was found that high EA-PGS scores were positively associated with better cognitive function, longer years of education, higher employment rates, and higher incomes. Especially in carriers of rare variants, high EA-PGS can partially counteract the adverse effects of these rare variants on cognitive function and socioeconomic status. For example, among individuals with at least one rare variant, those with EA-PGS in the high quantile (above 70th percentile) exhibited similar mobile intelligence test scores to controls without rare variants. This suggests that EA-PGS can counteract the negative effects of rare variants to some extent. Using multivariate regression analysis, studies showed that individuals with high EA-PGS performed better across multiple cognitive and socioeconomic phenotypes after controlling for age, sex, and principal component analysis (PCA). Specifically, in individuals with at least one rare DD variant, high EA-PGS was significantly associated with improved cognitive performance and socioeconomic status. This result applies not only to individuals with a single rare variant, but also to individuals with multiple rare variants.
Biological Explanation of EA-PGS Explains that EA-PGS may indirectly affect an individual's cognitive ability and learning ability by enhancing or regulating the expression of genes associated with cognition and learning. This may involve key biological pathways such as neurodevelopment and synaptic function, which are closely linked to educational achievement.
The mitigating effect of EA-PGS underscores the importance of considering an individual's overall genetic background in genetic counseling for rare diseases and other genetic disorders. This finding not only provides a potential strategy to mitigate the negative effects of rare genetic variants, but also provides direction for future research to further explore how to optimize treatment strategies by modulating genetic background, and how polygenic scores can be used to improve an individual's quality of life and healthy outcomes.
Phenotypic "deviators" versus genetic risk phenotypic "deviators" are individuals whose genetic susceptibility predictions are significantly inconsistent with the observed phenotype. In this study, special attention was paid to individuals with higher Educational Attainment Polygenic Score (EA-PGS) but lower cognitive function scores, and lower EA-PGS scores but higher cognitive function scores. Using UKB's large-scale dataset, the researchers identified phenotypic 'deviators' and analysed the association of these individuals with genetic variants in rare developmental disorders (DD). For example, it was found that in individuals with the highest EA-PGS decile but the lowest fluid intelligence score (0 or 1), the carrier rate of rare DD variants was significantly higher than that of individuals with higher mobile intelligence scores in the same EA-PGS quanile.
Statistical analysis of the association between rare variants and phenotypic deviations showed that individuals with high EA-PGS but low cognitive function had a 1.68-fold higher probability of carrying rare DD variants (95% CI, 1.13–2.50; P = 0.01), and those in the high EA-PGS quantile but without educational qualifications had a 1.22-fold carrier rate for the rare variant compared with non-carriers (95% CI, 1.10–1.35; P = 0.00006）。 These results suggest that rare genetic variants may be an important factor contributing to the inconsistency of genetic susceptibility to phenotypic expression.
Biological mechanisms that influence the presence of phenotypic "deviators" may be related to rare variants influencing specific biological pathways that are closely related to cognitive function and educational achievement. For example, rare variants may affect neuronal function and synaptic connections, which can affect information processing and learning. In addition, these variants may affect an individual's cognitive performance by altering brain structure or the way neurochemical signaling is transmitted.
Potential limitationsSelection bias and representativeness issuesThe UK Biobank (UKB), while a widely used large dataset, is not fully representative of the genetic and environmental diversity of the entire UK or wider population. Participants in UKB generally had higher socioeconomic status and better health status, which may affect the generalizability of the findings. In addition, patients with rare diseases or individuals with severe genetic defects may be underestimated in this cohort.
Underconsideration of genetic diversity studies have focused primarily on individuals of European ancestry, which limits the ability to discover genetic markers that can be broadly applied to other races or populations. Genetic differences between populations may result in significant differences in the frequency and impact of rare variants, and therefore, the findings may not be applicable to people of non-European ancestry.
The interaction between genetic and environmental factorsAlthough the influence of genetic factors on phenotype has been considered, the possible interaction between environmental factors and genetic factors has not been fully considered. Environmental factors, such as educational opportunities, lifestyle habits, and socioeconomic status, may influence or modify the phenotypic effects of genetic variation. The exclusion of these factors may result in inaccurate estimates of genetic risk.
Functional interpretation of rare variants: This study relies on exome sequencing to identify loss-of-function (LoF) and deleterious missense variants, but the exact biological impact on these variants remains limited. Some rare variants may be misclassified as deleterious, when in fact they may be benign or functionally unknown. In addition, the function and impact of rare variants in non-coding regions are often more difficult to predict and validate.
Statistical and multiplexing testing issues Due to the nature of rare variants, especially those with very low frequencies, studies may lack sufficient statistical power in some analyses to detect true genetic effects. In addition, considering that multiple comparisons of multiple phenotypes were made, there may be an increased risk of false-positive results being found. Although methods such as Bonferroni correction are used to control for family error rates, these corrections can be too strict, resulting in some true correlations not being identified.
Potential Research Directions: The association between rare variants and phenotypic expression has been shown to show that individuals with multiple rare variants in monogenic developmental disorders (DDs) have more significant phenotypic effects than single variant carriers. Future studies can further explore the specific mechanisms of different types of rare variants, such as missense variants (missense) and loss-of-function variants (LoF), on different phenotypic characteristics.
The interaction between common and rare variants showed that the educational achievement polymorphism score (EA-PGS) had a cumulative effect with the phenotypic expression of rare DD variants. This suggests that common variants can affect the expression of rare variants by adjusting phenotypic thresholds. Future studies could explore more interactions between common and rare variants and how they work together to influence disease susceptibility and phenotypic variability.
Identification and functional analysis of rare variants in population cohort studiesIn large population cohorts such as UK Biobank, identifying phenotype-related rare variants is a challenge. Through the use of whole-exome sequencing and microarray data, studies have identified the phenotypic impact of rare variants associated with DD in non-clinical populations. Future studies can leverage a wider range of population data to improve the precision of rare variant detection and the depth of functional analysis.
Genetic research across racial and geographic groupsCurrent research is primarily based on individuals of European ancestry, and can be extended to other ethnic and geographic groups in the future to study how genetic background influences phenotypic expression of rare and common variants in different populations, and how these genetic differences affect the global distribution of diseases and treatment strategies.
Link to original article
Kingdom R, Beaumont RN, Wood AR, Weedon MN, Wright CF. Genetic modifiers of rare variants in monogenic developmental disorder loci. Nat Genet. 2024 Apr 18. doi: 10.1038/s41588-024-01710-0. Epub ahead of print. PMID: 38637616.
https://www.nature.com/articles/s41588-024-01710-0
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