By Marta Koblańska, January 2, 2026, 15:00 Poland’s time, Photo: double helix of DNA, Pixabay
The lower the frequency of a disease-inducing gene variant, the larger the absolute effect in size; however, the growth is slower, according to the third most-cited study in 2024, published in Cell Genomics.
The third most-cited study of 2024, with 101 citations, of which the first authoris is Konrad J. Karczewski, originally published in the journal ,,Cell Genomics” (Impact Factor 11.1) in September 2022 under the title: ,,Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes” that is based on an analysis of UK Biobank resources, has shown the gene-based association between about 4500 different diseases and traits. However, as the authors point out, a gene considered harmful may have or may gain the potential to alleviate the strong effects that manifest as a disease.
The overall “expression” in phenotype that, in this case (the study purposes), means the disease accounts for about 6 percent, while the number is serving up 993,280,477 gene-level association statistics (across protein-coding 19,407 genes, up to 4 functional annotation sets, and 3 burden tests) and 28,158,190,538 single-variant association statistics across 8,074,878 exome variants. These statistics included a dataset of nearly 400,000 individuals of European ancestry and relatives, and 451,000 in total. To make an image of the study’s importance and a painted picture of Europeans’ health status, the authors note, that the four annotation categories comprise the,, predicted LoF (pLoF- the gene’s tolerance for function loss), missense (including low-confidence pLoF variants and in-frame insertions or deletions [indels]), synonymous, and the combination pLoF or missense group, resulting in the mentioned 8,074,878 variants and 75,767 groups for association testing.
The main conclusion of the paper is that we may be genetically vulnerable/predisposed to a disease, which is influenced by natural selection (negative in the case of the most severe manifestations). – However, the process of the negative selection will tend to decrease the frequency of functionally damaging variants, suggesting that variants with large effect sizes are more likely to be rare, according to scientists.
Some interpretations of the study suggest that evolution has established its own security checkpoints. In simpler terms, we may accept a slightly lower overall health status among a larger population to allow for the survival of individuals with rare but more severe illnesses.
In line with the study, the phenotype, thus the expression of diseases in the case of the single-gen variant, will be mainly shown in endocrinometabolic, digestive, skin/subcutaneous, and musculoskeletal malformations, as well as circulatory, nervous, and eye problems. The good news is that neoplasms, which can lead to cancer, tend to stabilize. Nonetheless, the outcomes of health problems that originate from a certain impairment due to genes’ mixture can be similar to those revealed for single-gene variance.
What does this mean? There may be additional associations between certain numbers and diseases or developmental delays; however, these associations are not expected to alter the genetic information that we all carry. This allows the genes inhibiting health burdens to continue functioning. Although scientists have observed a correlation with key genes that are considered the most significant, they indicate that these genes are more likely to be associated with a phenotype (6.38%) compared to a frequency-matched set of genes. That reversed association (a correlation between selection against the tolerance of a gene function loss, which may be high or low) means that even if we are carrying a harmful gene, it does not need to be expressed/doesn’t need to impact the gene’s structure/ morphology/physiology, or behaviour/performance.
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