Copy number variants increase the risk of internalising and cardiometabolic multimorbidity

Abstract Background Internalising and cardiometabolic multimorbidity (ICM-MM) represents a major clinical challenge, negatively impacting patients’ 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. Methods We used data from UK Biobank (ND-CNV N = 7,549, 1.62%). ICM-MM was identified using electronic healthcare records (primary care records and hospital episode statistics). 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 or presence of a deletion versus a duplication, and we tested the association of dosage-sensitive genes within ND-CNVs with ICM-MM. Results The presence of ND-was associated with ICM-MM (OR(CI) ranging from 1.21 (1.13-1.31) for any internalising condition and hypertension to 1.57 (1.38-1.77) for any internalising condition and T2D). Female participants with ND-CNV were more likely to have any cardiometabolic condition and 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 significantly associated with ICM-MM. Conclusions ND-CNVs increase the likelihood of ICM-MM, with evidence of sex differences and stronger effects for deletions. Increased clinical awareness can help ameliorate this risk and offer opportunities for early intervention and tailored healthcare approaches. Key messages • Copy number variants increase the risk of developing internalising and cardiometabolic multimorbidity. • There are sex differences in the risk conferred by copy number variants.