Genetic modifiers of rare variants in monogenic developmental disorder loci

Kingdom, Rebecca; Beaumont, Robin N.; Wood, Andrew R.; Weedon, Michael N.; Wright, Caroline F.

doi:10.1038/s41588-024-01710-0

Cited by 9 publications

(1 citation statement)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed an increase in the proportion of disease genes over evolutionary time (Figure 1a and 1c), suggesting that gene age impacts disease susceptibility—a trend consistent with earlier studies (Domazet-Lošo and Tautz 2008). Recent advances in medical genetics have revealed that Mendelian disorders are predominantly influenced by rare variants due to their significant phenotypic effects, a rational underlying the widespread use of burden tests in the field (Lee et al 2014; Guo et al 2018; Kingdom et al 2024). However, the correlation between gene age and rare variant burden remains elusive.…”

Section: Resultsmentioning

confidence: 99%

Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.

Chen,

Landback,

Arsala

et al. 2023

Preprint

View full text Add to dashboard Cite

New genes (or young genes) are structural novelties pivotal in mammalian evolution. Their phenotypic impacts on humans, however, remain elusive due to the technical and ethical complexities in functional studies. Through combining gene age dating with Mendelian disease phenotyping, our research reveals a steady integration of new genes with biomedical phenotypes into the human genome over macroevolutionary timescales (∼0.07% per million years). Despite this stable pace, we observe distinct patterns in phenotypic enrichment, pleiotropy, and selective pressures shaped by different gene ages. Notably, young genes show significant enrichment in the male reproductive system, indicating strong sexual selection. Young genes also exhibit functions in tissues and systems potentially linked to human phenotypic innovations, such as increased brain size, musculoskeletal phenotypes, and color vision. Our findings further reveal increasing levels of pleiotropy over evolutionary time, which accompanies stronger selective constraints. We propose a “pleiotropy-barrier” model that delineates different potentials for phenotypic innovation between young and older genes subject to natural selection. Our study demonstrates that evolutionary new genes are critical in influencing human reproductive evolution and adaptive phenotypic innovations driven by sexual and natural selection, with low pleiotropy as a selective advantage.

show abstract

Section: Resultsmentioning

confidence: 99%

Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.

Chen,

Landback,

Arsala

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Polygenic scores stratify neurodevelopmental copy number variant carrier cognitive outcomes in the UK Biobank

Dinneen,

Ní Ghrálaigh,

Ormond

et al. 2024

npj Genom. Med.

View full text Add to dashboard Cite

Rare copy-number variants associated with neurodevelopmental conditions (ND-CNVs) exhibit variable expressivity of clinical, physical, behavioural outcomes. Findings from clinically ascertained cohorts suggest this variability may be partly due to additional genetic variation. Here, we assessed the impact of polygenic scores (PGS) and rare variants on ND-CNV carrier fluid intelligence (FI) scores in the UK Biobank. Greater PGS for cognition (PS Cog ) and educational attainment (PS EA ) is associated with increased FI scores in all ND-CNVs ( n = 1317), 15q11.2 del. ( n = 543), and 16p13.11 dup. carriers ( n = 275). No association of rare variants associated with intellectual disability, autism, or putatively loss-of-function, brain-expressed genes was found. Positive predictive values in the first deciles of PS cog and PS EA showed a two- to five-fold increase in the rate of low FI scores compared to baseline rates. These findings demonstrate that PGS can stratify ND-CNV carrier cognitive outcomes in a population-based cohort.

show abstract

Examining the role of common variants in rare neurodevelopmental conditions

Huang,

Wigdor,

Malawsky

et al. 2024

Nature

View full text Add to dashboard Cite

Although rare neurodevelopmental conditions have a large Mendelian component1, common genetic variants also contribute to risk2,3. However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents nor its interplay with rare variants. It is also unclear whether polygenic background affects risk directly through alleles transmitted from parents to children, or whether indirect genetic effects mediated through the family environment4 also play a role. Here we addressed these questions using genetic data from 11,573 patients with rare neurodevelopmental conditions, 9,128 of their parents and 26,869 controls. Common variants explained around 10% of variance in risk. Patients with a monogenic diagnosis had significantly less polygenic risk than those without, supporting a liability threshold model5. A polygenic score for neurodevelopmental conditions showed only a direct genetic effect. By contrast, polygenic scores for educational attainment and cognitive performance showed no direct genetic effect, but the non-transmitted alleles in the parents were correlated with the child’s risk, potentially due to indirect genetic effects and/or parental assortment for these traits4. Indeed, as expected under parental assortment, we show that common variant predisposition for neurodevelopmental conditions is correlated with the rare variant component of risk. These findings indicate that future studies should investigate the possible role and nature of indirect genetic effects on rare neurodevelopmental conditions, and consider the contribution of common and rare variants simultaneously when studying cognition-related phenotypes.

show abstract

Genetic modifiers of rare variants in monogenic developmental disorder loci

Cited by 9 publications

References 51 publications

Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.

Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.

Polygenic scores stratify neurodevelopmental copy number variant carrier cognitive outcomes in the UK Biobank

Examining the role of common variants in rare neurodevelopmental conditions

Contact Info

Product

Resources

About