Neurodevelopmental copy number variants increase risk of internalising and cardiometabolic multimorbidity: findings from UK Biobank

BackgroundInternalising and cardiometabolic multimorbidity (ICM-MM) represents a major clinical challenge, negatively impacting life expectancy and quality of life and resulting in considerable healthcare costs. Individuals with a copy number variant associated with increased risk of neurodevelopmental conditions (ND-CNV) are more likely to develop mental or physical ill health, however the effects on ICM-MM remain poorly understood. MethodsWe used data from UK Biobank (ND-CNV N= 7,549, 1.62%). ICM-MM was identified using electronic healthcare records. It was defined as combinations of any internalising condition (either depression, anxiety or somatoform disorder) with each of five cardiometabolic conditions (hypertension, dyslipidemia, obesity, type 2 diabetes and chronic kidney disease). We also studied whether ICM-MM risk in those with ND-CNV differed by sex, presence of a deletion versus a duplication and we established associations of dosage-sensitive genes within ND-CNVs with ICM-MM. Finally, we explored the interaction between presence of ND-CNV and polygenic risk scores (PRSs) of internalising and cardiometabolic traits on ICM-MM risk. ResultsThe presence of ND-CNV was associated with ICM-MM (OR range 1.21-1.57). Female participants with ND-CNV were more likely to have any internalising condition and T2D, and those with a deletion any internalising condition and obesity. The number of deleted haploinsufficient genes, but not duplicated triplosensitive genes, was associated with ICM-MM. No significant interactions between ND-CNVs and PRSs were found. ConclusionsThis is the first study to report that ND-CNVs increase the likelihood of ICM-MM, and we find evidence of sex differences and stronger effects for deletions. Increased clinical awareness can help ameliorate this risk.