Huge thanks to co-first author, Emma Wade
‪@emmaewade.bsky.social‬! Also grateful for the supervision of Hilary Martin @hilarycmartin.bsky.social and the contributions from all of our co-authors.

Our mediation analysis shows that both externalising behaviours and cognitive ability in childhood partially mediate the direct genetic effects of multiple PGIs and of deleterious rare variants on adolescent mental health symptoms - identifying childhood as a potential window for intervention.

A key methodological advantage is the use of Mendelian imputation to recover missing parental genotypes. This helps mitigate bias associated with non-random ascertainment of genotyped trios in these cohorts, over and above boosting power for association testing (See Extended Data Figure 1 and 2).

Our findings support existing evidence that associations between externalising symptoms and PGIs for externalising behaviours, ADHD, and the cognitive component of educational attainment are primarily explained by direct genetic effects.

Measures of deleterious rare variants explain additional variance in mental health symptoms beyond that accounted for by common genetic variation.

I’m most excited about our rare variant findings: a higher burden of deleterious protein-truncating variants is associated with increased mental health symptoms. Trio models indicated direct genetic effects on externalising in MCS and on internalising symptoms in ALSPAC.

Using newly generated exome-sequence data (and existing genotype array data) from three British birth cohorts, we integrated common and rare variant analyses with within‐family designs to provide new insight into the genetic architecture of early‐life mental health.

😂for sure!

11/ Special thank you to @hilarycmartin.bsky.social and Elizabeth Radford for supervising this work.

10/ I’d like to thank the patients, families and clinicians who contributed to DDD and Genomics England. As well as my co-first author, Patrick Campbell. Grateful to all other contributors: @qinqinhuang.bsky.social @sjlindsay.bsky.social @mehurles.bsky.social and others.

9/ The presence of a diagnostic genetic variant modifies the relationship between polygenic predisposition to education-related traits and gestational duration, suggesting that the nature of the diagnostic variant has the largest impact on risk of preterm delivery.

8/ The observed association between polygenic predisposition to education-related traits and prematurity is likely the result of genetically-influenced parental traits and  behaviours or confounders, rather than the direct effect of the child’s genotype on gestational duration.

7/ Both preterm and term probands are enriched for pathogenic de novo mutations. However, the fraction of cases explained by DNMs in known DD-associated genes is higher in term than preterm cases, while DNMs in as-yet-undiscovered genes contribute approximately equally to both groups.

6/ We also find that premature patients recruited for clinical sequencing are enriched for genetic diagnoses in certain genes and gene sets, implying that these warrant further investigation for an association with risk of preterm delivery at the population level.

5/ One of the key findings is that prematurity and diagnostic genetic variants act additively and independently to influence phenotypic severity in developmental disorders. Premature probands have more affected organ systems and delayed developmental milestone attainment compared to term probands.

4/ In this study, we combined data from the DDD study and the Genomics England 100,000 Genomes Project (21,712 individuals - 16% premature) to characterise the impact of preterm birth on phenotypic outcomes and to explore the contribution of rare and common genetic variation to preterm birth.

3/ Previous work from our team (www.nature.com/articles/s41...) showed that polygenic predisposition for lower educational attainment is associated with increased likelihood of preterm birth, which could potentially confound associations between prematurity and phenotypic outcomes in DD patients.

2/ Both genetic and environmental factors, including premature birth, contribute to the risk of developmental disorders (DDs), but the interplay between these factors in altering individuals’  phenotypic presentation is poorly understood.