Neurodevelopmental copy-number variants increase risk of internalizing and cardiometabolic multimorbidity: Findings from the UK Biobank

Internalizing 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. We used data from the UK Biobank (ND-CNV N = 7,549, 1.62%) to examine the effect of ND-CNVs on ICM-MM. ICM-MM was defined as a combination of any internalizing condition (depression, anxiety, or somatic symptom disorder) with each of five cardiometabolic conditions (hypertension, dyslipidemia, obesity, type 2 diabetes (T2D), and chronic kidney disease). We also studied whether ICM-MM risk in those with ND-CNVs differed by sex or presence of a deletion versus a duplication. We established associations between dosage-sensitive genes within ND-CNVs and ICM-MM and explored the interaction between the presence of ND-CNVs and polygenic risk scores (PRSs) of internalizing and cardiometabolic traits on ICM-MM risk. The presence of ND-CNVs was associated with ICM-MM (odds ratio [OR] range: 1.21-1.57). Female participants with ND-CNVs were more likely to have any internalizing condition and T2D, and those with a deletion were more likely to have any internalizing condition and obesity. The number of deleted haploinsufficient genes, but not duplicated triplosensitive genes, was associated with ICM-MM. No interactions between ND-CNVs and PRSs were found. We find that 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.