“Genetic Modifiers of Rare Variants in Monogenic Developmental Disorder Loci”, 2024-04-18 ():
Rare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DDs) and have also been shown to cause milder subclinical phenotypes in population cohorts. Here, we show that carrying multiple (2−5) rare damaging variants across 599 dominant DD genes has an additive adverse effect on numerous cognitive and socioeconomic traits in UK Biobank, which can be partially counterbalanced by a higher educational attainment polygenic score (EA-PGS).
Phenotypic deviators from expected EA-PGS could be partly explained by the enrichment or depletion of rare DD variants. Among carriers of rare DD variants, those with a DD-related clinical diagnosis had a substantially lower EA-PGS and more severe phenotype than those without a clinical diagnosis.
Our results suggest that the overall burden of both rare and common variants can modify the expressivity of a phenotype, which may then influence whether an individual reaches the threshold for clinical disease.
…Rare variant status and polygenic background additively contribute to phenotype and predict outliers
Intrigued by the presence of these apparently highly intelligent rare DD variant carriers, we further investigated phenotypic ‘deviators’ in whom the predicted genetic susceptibility was discordant with the observed phenotype44, for example, individuals with high EA-PGS but low fluid intelligence score and vice versa (Figure 4). This question has particular clinical relevance as it has previously been suggested that individuals with familial disease could be prioritized for genetic testing based on having a low-risk PGS because they may be more likely to have a single large-effect causal variant than individuals with a high-risk PGS whose disease could be more polygenic45, 46.
To investigate this hypothesis, we further split the UKB cohort into EA-PGS deciles and tested whether individuals whose low cognitive phenotype was discordant with their high EA-PGS were more likely to be rare DD variant carriers than the remainder of the UKB cohort. Individuals in the top EA-PGS decile but with low fluid intelligence (scores of 0–1⁄13) were more likely to be rare DD variant carriers (odds ratio (OR) = 1.68; 95% CI, 1.13–2.50; p = 0.01) (Figure 5a) when compared to those in the same EA-PGS decile who did not have a low fluid intelligence score, as were those in the top EA-PGS decile who had no educational qualifications on record (OR = 1.22; 95% CI, 1.10–1.35; p = 0.00006) (Figure 5b).
Following separation by rare DD variant class, we found that large multigenic deletions had a larger effect than any other type of rare DD variant (OR = 4.7; 95% CI, 1.73–12.95; p = 0.002), followed by multigenic duplications and then by pLoF variants (Supplementary Table 9).
We then investigated whether the opposite was also true, that is, whether those with an EA-PGS in the bottom decile but a high fluid intelligence score (11–13⁄13) were less likely to be rare variant carriers, and found that these individuals were nearly half as likely as others in the same decile to carry a rare DD variant (OR = 0.58; 95% CI, 0.38–0.87; p = 0.009).
Finally, we investigated whether a decrease in EA-PGS correlated with the likelihood of receiving a clinical diagnosis related to DD among the rare DD variant carriers identified in UKB.
The number of individuals identified within the 3 diagnostic categories (child DDs, n = 7,933; adult neuropsychiatric conditions, n = 19,004; and other mental health issues, n = 32,911) is likely to be an underestimate because of missing data or the absence of, or omissions in, individual hospital records available within UKB. Therefore, although individuals in any of these diagnostic categories were more likely to be rare DD variant carriers than the rest of UKB, the majority did not carry a rare variant in any of the DD genes, and many individuals with a rare DD variant did not have a corresponding diagnosis.
Despite these limitations, we found that, among rare DD variant carriers, those with a related clinical diagnosis across any of our 3 categories had a substantially lower EA-PGS than those without a diagnosis (Figure 6); rare DD variant carriers with adult neuropsychiatric disorders or mental health issues (but not child DDs) also had a higher schizophrenia or bipolar PGS (Supplementary Figure 5). Rare DD variant carriers with a diagnosis also had a larger phenotypic change than other rare variant carriers without a diagnosis; individuals with a rare DD variant and a related clinical diagnosis were more likely to be unable to work (OR = 6.66; 95% CI, 6.07–7.32; p = 4.51 ⨯ 10−308), less likely to have a degree (OR = 0.71; 95% CI, 0.66–0.76; p = 3.76 ⨯ 10−23) and less likely to be employed (OR = 0.33; 95% CI, 0.31–0.37; p = 2.07 ⨯ 10−143) than those who carried a rare DD variant but did not have a diagnosis recorded in UKB (Supplementary Table 10).
This suggests that both the aggregation of the overall number of rare DD variants carried and a lower EA-PGS can alter the overall expressivity of the phenotype toward reaching the threshold of clinical disease.