Genetic modifiers of rare variants in monogenic developmental disorder loci

Abstract

Rare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DD), and have been shown to cause milder sub-clinical phenotypes in population cohorts. To investigate potential genetic modifiers, we identified individuals in UK Biobank with predicted deleterious variants in 599 autosomal dominant DD genes, and found that carrying multiple rare variants in these genes had an additive adverse effect on numerous cognitive and socio-economic traits, which could be partially counterbalanced by a higher educational attainment polygenic score (EA-PGS). Amongst rare DD variant carriers, those with a DD-related clinical diagnosis had a substantially lower EA-PGS and more severe phenotype than those without. Our results suggest that the overall burden of both rare and common variants can modify the expressivity of a phenotype, which may influence whether an individual reaches the threshold for clinical disease.

Dissecting the contribution of common variants to risk of rare neurodevelopmental conditions

“…To test for possible shared genetic contributors to rare neurodevelopmental conditions and other brain-related traits and conditions, we calculated genetic correlations ( r g ) between them using our own and published GWAS meta-analyses. We observed the expected negative genetic correlations between neurodevelopmental conditions and educational attainment 37 (EA; r g =- 0.65 [-0.84, -0.47], p=4.9x10 - 12 ) and cognitive performance 37 (CP; r g =-0.56 [-0.73, -0.39], p=1.6x10 - 10 ), stronger in magnitude than those observed with the DDD GWAS alone, and a positive genetic correlation with schizophrenia 38 (SCZ; r g =0.27 [0.13, 0.40], p=9.7x10 - 5 ) ( Figure 1A ; Supplementary Table 4 ). Additionally, we detected significant genetic correlations (p<0.0038=0.05/13 traits) with several other mental health conditions including Attention-Deficit Hyperactive Disorder (ADHD) 41 ( r g =0.46 [0.28, 0.64], p=5.2x10 - 7 ), and with the non-cognitive component of educational attainment derived from GWAS-by-subtraction (NonCogEA) 42 ( r g =- 0.37 [-0.52, -0.22], p=1.2x10 - 6 ) ( Figure 1A ).…”

“…Preterm delivery (i.e. giving birth prematurely) 55 , which is a risk factor for neurodevelopmental conditions in the offspring 45–47 , showed significant genetic correlations with lower educational attainment (r g =- 0.30 [-0.39, -0.21], p=2.3x10 - 10 ), mirroring the epidemiological association 56 , and with neurodevelopmental conditions (r g =0.58 [0.18, 0.97], p=0.004) ( Extended Data Figure 8A , Supplementary Table 9 ). Premature birth was also associated with lower PGS EA in DDD ( Extended Data Figure 8B ).…”

“…In particular, this common variant contribution overlaps with polygenic risk for schizophrenia and for predisposition to reduced educational attainment and cognitive performance 6 . Accordingly, rare damaging variants in constrained genes, which play a major role in risk of rare neurodevelopmental conditions, are also associated with reduced educational attainment and cognitive performance and increased risk of mental health conditions in UK Biobank [8][9][10][11][12] . In this work, we seek to better understand the nature of common variant risk for rare neurodevelopmental conditions, its interplay with rare variants and its distribution amongst different patients and their parents.…”

“…We previously saw no significant difference in polygenic scores between patients with versus without a monogenic diagnosis 6 , but in this work, we anticipated that increased sample size and improved diagnostic rate 5,27 might improve power. Since rare variants associated with neurodevelopmental conditions appear to act additively with polygenic scores in affecting cognitive ability in UK Biobank 9,10 , we hypothesized that polygenic background would modify the penetrance of these inherited rare variants in families with neurodevelopmental conditions, as it does, for example, in the context of BRCA1/2 variants predisposing to breast cancer 28 .…”

Investigating the role of commoncis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders

“…Future studies should consider this hypothesis in larger datasets with direct measurements of expression and genome sequencing data to evaluate rare variants that could alter gene expression. They should also consider alternative explanations for this apparent incomplete penetrance of rare inherited variants, such as a modifying role of polygenic background 57 , epistasis, stochastic effects, alternative splicing, changing effects of these rare variants with age, or environmental factors.…”