Common variant contributions to neurodevelopmental risk in orofacial clefts

Rammos, Alexandros, Lewis, Sarah J., Davies, Amy, Wren, Yvonne, Humphries, Kerry, Sandy, Jonathan, Sharp, Gemma C., Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, van den Bree, Marianne B.M. ORCID: https://orcid.org/0000-0002-4426-3254 and Stergiakouli, Evie 2026. Common variant contributions to neurodevelopmental risk in orofacial clefts. Item availability restricted.

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Abstract

Background Children with cleft lip and/or palate (CL/P) experience increased rates of neurodevelopmental difficulties, including ADHD, autism spectrum disorder, and educational challenges. While rare neurodevelopmental copy number variants (ND-CNVs) are enriched in this population and associated with poorer outcomes, these variants are present in only a small proportion of children born with cleft. Whether shared common genetic variation contributes to neurodevelopmental comorbidities in CL/P remains unknown. Methods We investigated this question using data from 2,313 children with CL/P from the Cleft Collective and 7,913 population controls from the Millennium Cohort Study. We tested for shared genetic architecture using linkage disequilibrium score regression, examined associations between polygenic risk scores for eight cognitive, neurodevelopmental, and psychiatric traits and developmental and behavioural outcomes within the cleft population, compared polygenic risk scores between cases and controls, compared polygenic burden between ND-CNV carriers and non-carriers, and employed two-sample Mendelian randomization to test whether genetic liability to cleft causally influences neurodevelopmental outcomes. Results Linkage disequilibrium score regression revealed little evidence of genetic correlations between CL/P and any of the eight traits examined. Within the cleft population, polygenic risk scores demonstrated expected associations with developmental and behavioural outcomes; however, children with CL/P did not have increased polygenic risk scores for ADHD, autism, depression, anxiety, schizophrenia, bipolar disorder, or lower scores for educational attainment or intelligence compared to controls. Mendelian randomization provided no robust evidence that genetic liability to cleft causally influences neurodevelopmental outcomes. ND-CNV carriers did not differ from non-carriers in polygenic burden. Conclusions The increased neurodevelopmental risk observed in CL/P does not appear to be primarily explained by shared common genetic architecture with psychiatric disorders, in contrast to established rare variant contributions. Polygenic risk scores for neurodevelopmental traits predict behavioural outcomes within the cleft population similarly to the general population, suggesting these genetic factors may be operating independently of cleft status while remaining clinically relevant.

Item Type:	UNSPECIFIED
Date Type:	Publication
Status:	In Press
Schools:	Schools > Medicine
Publisher:	BioMed Central
Date of Acceptance:	18 August 2026
Last Modified:	14 Sep 2026 15:15
URI:	https://orca.cardiff.ac.uk/id/eprint/189571

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